The present invention is compounds useful in treating Alzheimer""s disease and other similar diseases.
Alzheimer""s disease (AD) is a progressive degenerative disease of the brain primarily associated with aging which results in loss of memory and orientation. As the disease progresses, motor, sensory and linguistic abilities are also affected until there is global impairment of multiple cognitive functions. These cognitive losses occur gradually, but typically lead to severe impairment and eventual death in the range of four to twelve years.
Alzheimer""s disease is characterized by two major pathologic observations in the brain: neurofibrillary tangles and amyloid (or neuritic) plaques, particularly in those regions involved with memory and cognition (see, Selkoe D J, xe2x80x9cTranslating cell biology into therapeutic advances in Alzheimer""s disease,xe2x80x9d Nature ( ENGLAND ) Jun. 24, 1999, 399 (6738 Suppl) pA23-31). Smaller numbers of these lesions in a more restricted anatomical distribution are found in the brains of most aged humans who do not have clinical AD. Amyloid plaque and neurofibrillary tangles are comprised predominantly of an aggregate of a peptide fragment known as beta-amyloid peptide (Axcex2).
Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down""s Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.
Neurofibrillary tangles are characterized as networks of microtubules and microfilaments which were once structural supports running symmetrically through the nerve cells transporting nutrients, but have degenerated into dysfunctional tangled masses. They can be described histologically as non-membrane bound bundles containing paired, helically wound filaments (PHF) that are approximately 10 nm in length and located in the perinuclear cytoplasm of certain neurons. Major components of paired helical filaments are highly phosphorylated tau proteins (PHF-tau) of 60 kDa, 64 kDa and 68 kDa. Tau belongs to the family of microtubule-associated proteins and plays a role in the microtubule assembly and stabilization. In certain other neurodegenerative disorders, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and Pick""s disease, hyperphosphorylated tau proteins also accumulate in brain tissue in association with abnormal filaments. Recent research indicates that the pattern of hyperphosphorylation and the resulting ultrastructure of the helical filaments are somewhat different in each type of disease.
At present there are no effective treatments for halting, preventing or reversing the progression of Alzheimer""s disease; only treatments that palliate symptoms are thus far available. Therefore, there is an urgent need for pharmaceutical agents capable of slowing the progression of Alzheimer""s disease and/or preventing it in the first place.
United States Patents
1. U.S. Pat. No. 5,733,882
2. U.S. Pat. No. 4,880,781
3. U.S. Pat. No. 5,663,200
4. U.S. Pat. No. 5,807,891
5. U.S. Pat. No. 5,935,976
6. U.S. Pat. No. 4,668,770
7. U.S. Pat. No. 6,013,658
8. U.S. Pat. No. 5,162,538
International Patents and Patent Applications
1. WO 93/02057
2. WO 93/17003
3. EP 0320205
4. WO 87/02986
5. WO 89/01488
6. WO 92/17490
7. WO 89/00161
8. GB 2203740
9. EP 0337714
10. DE 3721855
11. EP 0209897
12. EP 0264106
13. WO 8704349
14. JP 7-126286
15. EP 0212903
16. JP 297664
17. EP 0372537
18. WO 97/30072
19. EP 0437729
Literature References
1. Sakurai, M., et al., Chem. Pharm. Bull. (1993), 41, 8, 1378-1386.
2. Sakurai, M., et al., Tetrahedron Lett. (1993), 34, 37, 5939-5942.
3. Diederich, A. M., et al., Tetrahedron Lett. (1993), 34, 39, 6169-6172.
This invention is directed to the novel compounds of formula 1 that are useful in treating Alzheimer""s disease and other similar diseases.
Disclosed are hydroxyethylene compounds of the formula (XII): 
where R1 is:
(I) C1-C6 alkyl,
(II) C1-C6 alkyl-S-alkyl
(III) C1-C6 alkyl-(C2-C6 alkenyl),
(IV) xe2x80x94(CH2)0-6-alkyl -(R1-aryl) where R1-aryl is unsubstituted or substituted with:
(A) C1-C6 alkyl,
(B) xe2x80x94CF3,
(C) xe2x80x94F, Cl, xe2x80x94Br or xe2x80x94I,
(D) C1-C3 alkoxy,
(E) xe2x80x94Oxe2x80x94CF3,
(F) xe2x80x94NH2,
(G) xe2x80x94OH, or
(H) xe2x80x94Cxe2x89xa1N,
(V) xe2x80x94(CH2)0-6-alkyl -(R1-heteroatyl) where R1-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) inidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) xcex2-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrofuranyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
xe2x80x83where the R1-heteroaryl group is bonded to -alkyl- by any ring atom of the parent RN-heteroaryl group substituted by hydrogen such that the new bond to the R1-heteroaryl group replaces the hydrogen atom and its bond, where R1-heteroaryl is unsubstituted or substituted with:
(1) C1-C3 alkyl,
(2) xe2x80x94CF3,
(3) xe2x80x94F, Cl, xe2x80x94Br, or I,
(4) C1-C3 alkoxy,
(5) xe2x80x94Oxe2x80x94CF3,
(6) xe2x80x94NH2,
(7) xe2x80x94OH, or
(8) xe2x80x94Cxe2x89xa1N,
(VI) xe2x80x94(R1-heteroaryl) where R1-heteroaryl is as defined above,
(VII) xe2x80x94C1-C5 alkyl-(R1-heterocycle) where R1-heterocycle is:
(A) morpholinyl,
(B) thiomorpholinyl,
(C) thiomorpholinyl S-oxide,
(D) thiomorpholinyl S,S-dioxide,
(E) piperazinyl,
(F) homopiperazinyl,
(G) pyrrolidinyl,
(H) pyrrolinyl,
(I) tetrahydropyranyl,
(J) piperidinyl,
(K) tetrahydrofuranyl, or
(L) tetrahydrothiophenyl,
xe2x80x83where the R1-heterocycle group is bonded by any atom of the parent R1-heterocycle group substituted by hydrogen such that the new bond to the R1 heteroaryl group replaces the hydrogen atom and its bond, where R1-heterocycle is unsubstituted or substituted with:
(1) xe2x95x90O
(2) C1-C3 alkyl,
(3) xe2x80x94CF3,
(4) xe2x80x94F, Cl, xe2x80x94Br or xe2x80x94I,
(5) C1-C3 alkoxy,
(6) xe2x80x94Oxe2x80x94CF3,
(7) xe2x80x94NH2,
(8) xe2x80x94OH, or
(9) xe2x80x94Cxe2x89xa1N, or
(VIII) xe2x80x94R1-heterocycle with R1-heterocycle as defined above;
where R2 is:
(I) xe2x80x94H,
(II) alkyl, or
(III) xe2x80x94C1-C5 alkyl-R2-1 where R2-1 is cycloalkyl, R1-aryl or R1-heteroaryl where R1-aryl and R1-heteroaryl are as defined above,
where RN is:
(I) RN-1xe2x80x94XNxe2x80x94 where XN is:
(A) xe2x80x94COxe2x80x94,
(B) xe2x80x94SO2xe2x80x94,
(C) xe2x80x94(CRxe2x80x2Rxe2x80x3)1-6 where Rxe2x80x2 and Rxe2x80x3 are the same or different and are xe2x80x94H or C1-C4 alkyl,
(D) xe2x80x94COxe2x80x94(CRxe2x80x2Rxe2x80x3)1-6xe2x80x94XN-1 where XN-1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NRxe2x80x2Rxe2x80x3xe2x80x94 and where Rxe2x80x2 and Rxe2x80x3 are as defined above, or
(E) a single bond;
where RN-1 is:
(A) RN-aryl where RN-aryl is unsubstituted or substituted with:
(1) C1-C6 alkyl,
(2) xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(3) xe2x80x94OH,
(4) xe2x80x94NO2,
(5) xe2x80x94COxe2x80x94OH,
(6) xe2x80x94Cxe2x89xa1N,
(7) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are:
(a) xe2x80x94H,
(b) xe2x80x94C1-C6 alkyl unsubstituted or substituted with
(i) xe2x80x94OH, or
(ii) xe2x80x94NH2,
(c) xe2x80x94C1-C6 alkyl unsubstituted or substituted with xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(d) xe2x80x94C3-C7 cycloalkyl,
(e) xe2x80x94(C1-C2 alkyl)-(C3-C7 cycloalkyl),
(f) xe2x80x94(C1-C6 alkyl)xe2x80x94Oxe2x80x94(C1-C3 alkyl),
(g) xe2x80x94C1-C6 alkenyl with one or two double bonds,
(h) xe2x80x94C1-C6 alkynyl with one or two triple bonds,
(i) xe2x80x94C1-C6 alkyl chain with one double bond and one triple bond,
(j) xe2x80x94R1-aryl where R1-aryl is as defined above, or
(k) xe2x80x94R1-heteroaryl where R1-heteroaryl is as defined above,
(8) xe2x80x94COxe2x80x94(C3-C12 alkyl),
(9) xe2x80x94COxe2x80x94(C3-C6 cycloalkyl),
(10) xe2x80x94COxe2x80x94R1-heteroaryl where R1-heteroaryl is as defined above,
(11) xe2x80x94COxe2x80x94R1-heterocycle where R1-heterocycle is as defined above,
(12) xe2x80x94COxe2x80x94RN-4 where RN-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with C1-C3 alkyl,
(13) xe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is:
(a) alkyl, or
(b) xe2x80x94(CH2)0-2xe2x80x94(R1-aryl) where R1-aryl is as defined above,
(14) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are as defined above,
(15) xe2x80x94SOxe2x80x94(C1-C8 alkyl),
(16) xe2x80x94SO2xe2x80x94(C3-C12 alkyl),
(17) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is as defined above,
(18) xe2x80x94NHxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(19) xe2x80x94Nxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(20) xe2x80x94N(C1-C3 alkyl)-COxe2x80x94RN-5 where RN-5 is as defined above,
(21) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 can be the same or different and are as defined above,
(22) xe2x80x94RN-4 where RN-4 is as defined above,
(23) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(24) xe2x80x94Oxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(25) xe2x80x94Oxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(26) xe2x80x94Oxe2x80x94(C1-C6 alkyl),
(27) xe2x80x94Oxe2x80x94(C2-C5 alkyl)-COOH,
(28) xe2x80x94Sxe2x80x94(C1-C6 alkyl),
(29) C1-C6 alkyl unsubstituted or substituted with halo,
(30) xe2x80x94Oxe2x80x94(C1-C6 alkyl unsubstituted or substituted with halo), or
(31) xe2x80x94O- xcfx86,
(B) xe2x80x94RN-heteroaryl where RN-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) imidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) xcex2-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrothienyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
xe2x80x83where the RN-heteroaryl group is bonded by any atom of the parent RN-heteroaryl group substituted by hydrogen such that the new bond to the RN-heteroaryl group replaces the hydrogen atom and its bond, where N-heteroaryl is unsubstituted or substituted with:
(1) C1-C6 alkyl,
(2) xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(3) xe2x80x94OH,
(4) xe2x80x94NO2,
(5) xe2x80x94COxe2x80x94OH,
(6) xe2x80x94Cxe2x89xa1N,
(7) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are:
(a) xe2x80x94H,
(b) xe2x80x94C1-C6 alkyl unsubstituted or substituted with:
(i) xe2x80x94OH, or
(ii) xe2x80x94NH2,
(c) xe2x80x94C1-C6 alkyl substituted or substituted with xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(d) xe2x80x94C3-C7 cycloalkyl,
(e) xe2x80x94(C1-C2 alkyl)xe2x80x94(C3-C7 cycloalkyl),
(f) xe2x80x94(C1-C6 alkyl)xe2x80x94Oxe2x80x94(C1-C3 alkyl),
(g) xe2x80x94C1-C6 alkenyl with one or two double bonds,
(h) xe2x80x94C1-C6 alkynyl with one or two triple bonds,
(i) xe2x80x94C1-C6 alkyl chain with one double bond and one triple bond,
(j) xe2x80x94R1-aryl where R1-aryl is as defined above, or
(k) xe2x80x94R1-heteroaryl where R1-heteroaryl is as defined above,
(8) xe2x80x94COxe2x80x94(C3-C12 alkyl),
(9) xe2x80x94COxe2x80x94(C3-C6 cycloalkyl),
(10) xe2x80x94COxe2x80x94R1-heteroaryl where R1-heteroaryl is as defined above,
(11) xe2x80x94COxe2x80x94R1-heterocycle where R1-heterocycle is as defined above,
(12) xe2x80x94COxe2x80x94RN-4 where RN-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with C1-C3 alkyl,
(13) xe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is:
(a) C1-C6 alkyl, or
(b) xe2x80x94(CH2)0-2xe2x80x94(R1-aryl) where R1-aryl is as defined above,
(14) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are as defined above,
(15) xe2x80x94SOxe2x80x94(C1-C8 alkyl),
(16) xe2x80x94SO2(C3-C12 alkyl),
(17) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is as defined above,
(18) xe2x80x94NHxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(19) xe2x80x94Nxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(20) xe2x80x94N(C1-C3 alkyl)-COxe2x80x94RN-5 where RN-5 is as defined above,
(21) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 can be the same or different and are as defined above,
(22) xe2x80x94RN-4 where RN-4 is as defined above,
(23) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(24) Oxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(25) xe2x80x94Oxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(26) xe2x80x94Oxe2x80x94(C1-C6 alkyl),
(27) xe2x80x94Oxe2x80x94(C2-C5 alkyl)-COOH, or
(28) xe2x80x94Sxe2x80x94(C1-C6 alkyl),
(C) xe2x80x94RN-arylxe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(D) xe2x80x94RN-arylxe2x80x94RN-heteroaryl where xe2x80x94RN-aryl and xe2x80x94RN-heteroaryl are as defined above,
(E) xe2x80x94RN-heteroatylxe2x80x94RN-aryl where xe2x80x94RN-aryl and xe2x80x94RN-heteroaryl are as defined above,
(F) xe2x80x94RN-heteroarylRN-heteroaryl where RN-heteroaryl is as defined above,
(G) xe2x80x94RN-arylxe2x80x94Oxe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(H) xe2x80x94RN-arylxe2x80x94Sxe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(I) xe2x80x94RN-heteroarylxe2x80x94Oxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(J) xe2x80x94RN-heteroarylxe2x80x94Sxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(K) xe2x80x94RN-arylxe2x80x94COxe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(L) xe2x80x94RN-arylxe2x80x94COxe2x80x94RN-heteroaryl where xe2x80x94RN-aryl and RN-heteroaryl are as defined above,
(M) xe2x80x94RN-arylxe2x80x94SO2RN-aryl where RN-aryl is as defined above,
(N) xe2x80x94RN-heteroarylxe2x80x94COxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(O) xe2x80x94RN-heteroarylxe2x80x94SO2xe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(P) xe2x80x94RN-arylxe2x80x94Oxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-aryl is as defined above,
(Q) xe2x80x94RN-arylxe2x80x94Sxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-aryl is as defined above,
(R) xe2x80x94RN-heteroarylxe2x80x94Oxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-heteroaryl is as defined above, or
(S) xe2x80x94RN-heteroarylxe2x80x94Sxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-heteroaryl is as defined above,
(II) xe2x80x94COxe2x80x94(C1-C6 alkyl) where alkyl is unsubstituted or substituted with:
(A) xe2x80x94OH,
(B) xe2x80x94C1-C6 alkoxy,
(C) xe2x80x94C1-C6 thioalkoxy,
(D) xe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is xe2x80x94H, C1-C6 alkyl or -xcfx86,
(E) xe2x80x94COxe2x80x94NRN-2 RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) xe2x80x94COxe2x80x94RN-4 where RN-4 is as defined above,
(G) xe2x80x94SO2xe2x80x94(C1-C8 alkyl),
(H) xe2x80x94SO2xe2x80x94NRN-2 RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) xe2x80x94NHxe2x80x94COxe2x80x94(C1-C6 alkyl),
(J) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is as defined above,
(K) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) xe2x80x94RN-4 where RN-4 is as defined above,
(M) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(N) xe2x80x94Oxe2x80x94COxe2x80x94NRN-8RN-8 where the RN-8 are the same or different and are as defined above, or
(O) xe2x80x94Oxe2x80x94(C1-C5 alkyl)-COOH,
(III) xe2x80x94COxe2x80x94(C1-C3 alkyl)xe2x80x94Oxe2x80x94(C1-C3 alkyl) where alkyl is unsubstituted or substituted with:
(A) xe2x80x94OH,
(B) xe2x80x94C1-C6 alkoxy,
(C) xe2x80x94C1-C6 thioalkoxy,
(D) xe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is xe2x80x94H, C1-C6 alkyl or -xcfx86,
(E) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) xe2x80x94COxe2x80x94RN-4 where RN-4 is as defined above,
(G) xe2x80x94SO2xe2x80x94(C1-C8 alkyl),
(H) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) xe2x80x94NHxe2x80x94COxe2x80x94(C1-C6 alkyl),
(J) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is as defined above,
(K) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) xe2x80x94RN-4 where RN-4 is as defined above,
(M) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(N) xe2x80x94Oxe2x80x94COxe2x80x94NRN-8RN-8 where the RN-8 are the same or different and are as defined above, or
(O) xe2x80x94Oxe2x80x94(C1-C5 alkyl)-COOH,
(IV) xe2x80x94COxe2x80x94(C1-C3 alkyl)xe2x80x94Sxe2x80x94(C1-C3 alkyl) where alkyl is:
(A) xe2x80x94OH,
(B) xe2x80x94C1-C6 alkoxy,
(C) xe2x80x94C1-C6 thioalkoxy,
(D) xe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is xe2x80x94H, C1-C6 alkyl or -xcfx86,
(E) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) xe2x80x94COxe2x80x94RN-4 where RN-4 is as defined above,
(G) xe2x80x94SO2xe2x80x94(C1-C8 alkyl),
(H) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) xe2x80x94NHxe2x80x94COxe2x80x94(C1-C6 alkyl),
(J) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is as defined above,
(K) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) xe2x80x94RN-4 where RN-4 is as defined above,
(M) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(N) xe2x80x94Oxe2x80x94COxe2x80x94NRN-8RN-8 where the RN-8 are the same or different and are as defined above, or
(O) xe2x80x94Oxe2x80x94(C1-C5 alkyl)-COOH,
(V) xe2x80x94COxe2x80x94CH(xe2x80x94(CH2)0-2xe2x80x94Oxe2x80x94RN-10)xe2x80x94(CH2)0-2xe2x80x94RN-aryl/RN-heteroaryl) where RN-aryl and RN-heteroaryl are as defined above, where RN-10 is selected from the group consisting of:
(A) xe2x80x94H,
(B) C1-C6 alkyl,
(C) C3-C7 cycloalkyl,
(D) C2-C6 alkenyl with one double bond,
(E) C2-C6 alkynyl with one triple bond,
(F) R1-aryl where R1-aryl is as defined above, or
(G) RN-heteroaryl where RN-heteroaryl is as defined above;
xe2x80x83where B is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94N(C1-C6 alkyl)-;
where Rc is:
(I) C1-C8 alkyl unsubstituted or substituted with xe2x80x94OH, xe2x80x94O- xcfx86, halo, or (C1-C6 alkoxy unsubstituted or substituted with halo),
(II) xe2x80x94(CH2)0-3-alkyl-(C3-C7) cycloalkyl where cycloalkyl is unsubstituted or substituted with:
(A) C1-C3 alkyl unsubstituted or substituted with xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(B) xe2x80x94COxe2x80x94OH,
(C) xe2x80x94COxe2x80x94Oxe2x80x94(C1-C4 alkyl),
(D) xe2x80x94OH, or
(E) C1-C6 alkoxy,
(III) xe2x80x94(CH2)2-6xe2x80x94OH,
(IV) xe2x80x94(CRC-xRC-y)0-4xe2x80x94RC-aryl where RC-x and RC-y are xe2x80x94H, C1-C4 alkyl and xcfx86- and RC-aryl is the same as RN-aryl,
(V) xe2x80x94(CH2)0-4xe2x80x94RC-heteroaryl where RC-heteroaryl is the same as RN-heteroaryl,
(VI) xe2x80x94(CH2)0-4xe2x80x94RC-heterocycle where RC-heterocycle is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) isoxazolyl,
(Q) pyrazolyl,
(R) indolizinyl,
(S) indazolyl,
(T) benzothiazolyl,
(U) benzimidazolyl,
(V) benzofuranyl,
(W) furanyl,
(X) thienyl,
(Y) pyrrolyl,
(Z) oxadiazolyl,
(AA) thiadiazolyl,
(BB) triazolyl,
(CC) tetrazolyl,
(DD) 1,4-benzodioxan
(EE) purinyl,
(FF) oxazolopyridinyl,
(GG) imidazopyridinyl,
(HH) isothiazolyl,
(II) naphthyridinyl,
(JJ) cinnolinyl,
(KK) carbazolyl,
(LL) xcex2-carbolinyl,
(MM) isochromanyl,
(NN) chromanyl,
(OO) furazanyl,
(PP) tetrahydroisoquinoline,
(QQ) isoindolinyl,
(RR) isobenzotetrahydrofuranyl,
(SS) isobenzotetrahydrothienyl,
(TT) isobenzothiophenyl,
(UU) benzoxazolyl, or
(VV) pyridopyridinyl,
(VII) xe2x80x94C(RC-1)(RC-2)xe2x80x94COxe2x80x94NHxe2x80x94RC-3 where RC-1 and RC-2 are the same or different and are:
(A) xe2x80x94H,
(B) xe2x80x94C1-C6 alkyl,
(C) xe2x80x94(C1-C4 alkyl)-RCxe2x80x2-aryl where RCxe2x80x2-aryl is as defined for R1-aryl,
(D) xe2x80x94(C1-C4 alkyl)-RC-heteroaryl where RC-heteroaryl is as defined above,
(E) xe2x80x94(C1-C4 alkyl)-RC-heterocycle where RC-heterocycle is as defined above,
(F) xe2x80x94RC-heteroaryl where RC-heteroaryl is as defined above,
(G) xe2x80x94RC-heterocycle where RC-heterocycle is as defined above,
(H) xe2x80x94(CH2)1-4xe2x80x94OH,
(I) xe2x80x94(CH2)1-4xe2x80x94RC-4xe2x80x94(CH2)1-4xe2x80x94RCxe2x80x2-aryl where RC-4 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94xe2x80x94NHxe2x80x94, or xe2x80x94NRC-5xe2x80x94 where RC-5 is C1-C6 alkyl, and where RCxe2x80x2-aryl is defined above,
(J) xe2x80x94(CH2)1-4xe2x80x94RC-4xe2x80x94(CH2)1-4xe2x80x94RC-heteroaryl where RC-4 and RC-heteroaryl are as defined above, or
(K) xe2x80x94RCxe2x80x2-aryl where RCxe2x80x2-aryl is as defined above,
and where RC-3 is:
(A) xe2x80x94H,
(B) xe2x80x94C1-C6 alkyl,
(C) xe2x80x94RCxe2x80x2-aryl where RCxe2x80x2-aryl is as defined above,
(D) xe2x80x94RC-heteroaryl where RC-heteroaryl is as defined above,
(E) xe2x80x94RC-heterocycle where RC-heterocycle is as defined above,
(F) xe2x80x94(C1-C4 alkyl)-RCxe2x80x2-aryl where RCxe2x80x2-aryl is as defined above,
(G) xe2x80x94(C1-C4 alkyl)-RC-heteroaryl where RC-heteroaryl is as defined above, or
(H) xe2x80x94(C1-C4 alkyl)-RC-heterocycle where RC-heterocycle is as defined above,
(VIII) xe2x80x94CH(xcfx86)2,
(IX) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring where heteroaryl is as defined above and phenyl and heteroaryl are unsubstituted or substituted with:
(A) C1-C3 alkyl,
(B) xe2x80x94CF3,
(C) xe2x80x94F, Cl, xe2x80x94Br or xe2x80x94I,
(D) C1-C3 alkoxy,
(E) xe2x80x94OCF3,
(F) xe2x80x94NH2,
(G) xe2x80x94OH, or
(H) xe2x80x94Cxe2x89xa1N,
(X) xe2x80x94CH2xe2x80x94Cxe2x89xa1CH;
(XI) xe2x80x94(CH2)0-1xe2x80x94CHRC-5xe2x80x94(CH2)0-1-xcfx86 where RC-5 is:
(A) xe2x80x94OH, or
(B)xe2x80x94CH2xe2x80x94OH;
(XII) xe2x80x94CH(-xcfx86)-COxe2x80x94O(C1-C3 alkyl);
(XIII) xe2x80x94CH(xe2x80x94CH2xe2x80x94OH)xe2x80x94CH(xe2x80x94OH)-xcfx86-(xe2x80x94NO2;
(XIV) xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94OH;
(XV) xe2x80x94CH2xe2x80x94NHxe2x80x94CH2xe2x80x94CH(xe2x80x94Oxe2x80x94CH2xe2x80x94CH3)2;
(XVI) xe2x80x94(C2-C8) alkynyl; or
(XVII) xe2x80x94H; and pharmaceutically acceptable salts thereof.
Also disclosed are hydroxyethylene compounds of the formula (XII): 
where R1 is:
(I) C1-C6 alkyl, unsubstituted or substituted with one, two or three C1-C3 alkyl, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94OH, xe2x80x94NH2, xe2x80x94CN, xe2x80x94CF3, or xe2x80x94N3,
(II) xe2x80x94(CH2)1-2xe2x80x94Sxe2x80x94CH3,
(III) xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94CH3,
(IV) xe2x80x94CH2xe2x80x94(C2-C6 alkenyl) unsubstituted or substituted by one xe2x80x94F,
(V) xe2x80x94(CH2)0-3xe2x80x94(R1-aryl) where R1-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinyl unsubstituted or substituted on the aryl ring with one or two of the following substituents which can be the same or different:
(A) C1-C3 alkyl,
(B) xe2x80x94CF3,
(C) xe2x80x94F, Cl, xe2x80x94Br and xe2x80x94I,
(D) C1-C3 alkoxy,
(E) xe2x80x94Oxe2x80x94CF3,
(F) xe2x80x94NH2,
(G) xe2x80x94OH, or
(H) xe2x80x94Cxe2x89xa1N,
(VI) xe2x80x94(CH2)n1xe2x80x94(R1-heteroaryl) where n1 is 0, 1, 2, or 3 and R1-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) imidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) xcex2-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrothienyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
xe2x80x83where the R1-heteroaryl group is bonded to xe2x80x94(CH2)0-3xe2x80x94 by any ring atom of the parent RN-heteroaryl group substituted by hydrogen such that the new bond to the R1-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is unsubstituted or substituted with one or two:
(1) C1-C3 alkyl,
(2) xe2x80x94CF3,
(3) xe2x80x94F, Cl, xe2x80x94Br, or xe2x80x94I,
(4) C1-C3 alkoxy,
(5) xe2x80x94Oxe2x80x94CF3,
(6) xe2x80x94NH2,
(7) xe2x80x94OH, or
(8) xe2x80x94Cxe2x80x94N,
xe2x80x83with the proviso that when n1 is zero R1-heteroaryl is not bonded to the carbon chain by nitrogen, or
(VII) xe2x80x94(CH2)n1xe2x80x94(R1-heterocycle) where n1 is as defined above and R1-heterocycle is:
(A) morpholinyl,
(B) thiomorpholinyl,
(C) thiomorpholinyl S-oxide,
(D) thiomorpholinyl S,S-dioxide,
(E) piperazinyl,
(F) homopiperazinyl,
(G) pyrrolidinyl,
(H) pyrrolinyl,
(I) tetrahydropyranyl,
(J) piperidinyl,
(K) tetrahydrofuranyl, or
(L) tetrahydrothiophenyl,
xe2x80x83where the R1-heterocycle group is bonded by any atom of the parent R1-heterocycle group substituted by hydrogen such that the new bond to the R1-heteroaryl group replaces the hydrogen atom and its bond, where heterocycle is unsubstituted or substituted with one or two:
(1) xe2x95x90O,
(2) C1-C3 alkyl,
(3) CF3,
(4) xe2x80x94F, Cl, xe2x80x94Br and xe2x80x94I,
(5) C1-C3 alkoxy,
(6) xe2x80x94Oxe2x80x94CF3,
(7) xe2x80x94NH2,
(8) xe2x80x94OH, or
(9) xe2x80x94Cxe2x89xa1N,
xe2x80x83with the proviso that when n1 is zero R1-heterocycle is not bonded to the carbon chain by nitrogen;
where R2 is:
(I) xe2x80x94H,
(II) C1-C6 alkyl, or
(III) xe2x80x94(CH2)0-4xe2x80x94R2xe2x88x921 where R21 is (C3-C6)cycloalkyl, R1-aryl or R-1-heteroaryl where R1-aryl and R1-heteroaryl are as defined above,
where RN is:
(I) RN-1xe2x80x94XNxe2x80x94 where XN is:
(A)xe2x80x94COxe2x80x94,
(B) xe2x80x94SO2xe2x80x94,
(C) xe2x80x94(CRxe2x80x2Rxe2x80x3)1-6 where Rxe2x80x2 and Rxe2x80x3 are the same or different and are xe2x80x94H or C1-C4 alkyl,
(D) xe2x80x94COxe2x80x94(CRxe2x80x2Rxe2x80x3)1-6xe2x80x94XN-1 where XN-1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94NRxe2x80x2Rxe2x80x3xe2x80x94 and where Rxe2x80x2 and Rxe2x80x3 are as defined above,
(E) a single bond;
where RN-1 is:
(A) RN-aryl where RN-aryl is phenyl, 1-naphthyl and 2-naphthyl unsubstituted or substituted with one, two, three or four of the following substituents which can be the same or different and are:
(1) C1-C6 alkyl,
(2) xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(3) xe2x80x94OH,
(4) xe2x80x94NO2,
(5)xe2x80x94COxe2x80x94OH,
(6) xe2x80x94Cxe2x89xa1N,
(7) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are:
(a) xe2x80x94H,
(b) xe2x80x94C1-C6 alkyl unsubstituted or substituted with one
(i) xe2x80x94OH, or
(ii) xe2x80x94NH2,
(c) xe2x80x94C1-C6 alkyl unsubstituted or substituted with one to three xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(d) xe2x80x94C3-C7 cycloalkyl,
(e) xe2x80x94(C1-C2 alkyl)-(C3-C7 cycloalkyl),
(f) xe2x80x94(C1-C6 alkyl)xe2x80x94Oxe2x80x94(C1-C3 alkyl),
(g) xe2x80x94C1-C6 alkenyl with one or two double bonds,
(h) xe2x80x94C1-C6 alkynyl with one or two triple bonds,
(i) xe2x80x94C1-C6 alkyl chain with one double bond and one triple bond,
(j) xe2x80x94R1-aryl where R1-aryl is as defined above, or
(k) xe2x80x94R1-heteroaryl where R1-heteroaryl is as defined above,
(8) xe2x80x94COxe2x80x94(C3-C12 alkyl),
(9) xe2x80x94COxe2x80x94(C3-C6 cycloalkyl),
(10) xe2x80x94COxe2x80x94R1-heteroaryl where R1-heteroaryl, is as defined above,
(11) xe2x80x94COxe2x80x94R1-heterocycle where R1-heterocycle is as defined above,
(12) xe2x80x94COxe2x80x94RN-4 where RN-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with one or two C1-C3 alkyl,
(13) xe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is:
(a) C1-C6 alkyl, or
(b) xe2x80x94(CH2)0-2xe2x80x94(R1-aryl) where R1-aryl is as defined above,
(14) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are as defined above,
(15) xe2x80x94SOxe2x80x94(C1-C8 alkyl),
(16) xe2x80x94SO2(C3-C12 alkyl),
(17) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is as defined above,
(18) xe2x80x94NHxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(19) xe2x80x94Nxe2x80x94CSxe2x80x94N(C1C3 alkyl)2,
(20) xe2x80x94N(C1-C3 alkyl)-COxe2x80x94RN-5 where RN-5 is as defined above,
(21) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 can be the same or different and are as defined above,
(22) xe2x80x94RN-4 where RN-4 is as defined above,
(23) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(24) xe2x80x94Oxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(25) xe2x80x94Oxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(26) xe2x80x94Oxe2x80x94(C1-C6 alkyl),
(27) xe2x80x94Oxe2x80x94(C2-C5 alkyl)-COOH,
(28) xe2x80x94Sxe2x80x94(C1-C6 alkyl),
(29) C1-C6 alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 xe2x80x94F,
(30) xe2x80x94Oxe2x80x94(C1-C6 alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 xe2x80x94F, or
(31) xe2x80x94O-xcfx86,
(B) xe2x80x94RN-heteroaryl where RN-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) imidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) xcex2-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrothienyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
xe2x80x83where the RN-heteroaryl group is bonded by any atom of the parent RN-heteroaryl group substituted by hydrogen such that the new bond to the RN-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is unsubstituted or substituted with one or two:
(1) C1-C6 alkyl,
(2) xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(3) xe2x80x94OH,
(4) xe2x80x94NO2,
(5) xe2x80x94COxe2x80x94OH,
(6) xe2x80x94Cxe2x89xa1N,
(7) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are:
(a) xe2x80x94H,
(b) xe2x80x94C1-C6 alkyl unsubstituted or substituted with one
(i) xe2x80x94OH, or
(ii) xe2x80x94NH2,
(c) xe2x80x94C1-C6 alkyl unsubstituted or substituted with 1, 2, or 3 xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(d) xe2x80x94C3-C7 cycloalkyl,
(e) xe2x80x94(C1-C2 alkyl)-(C3-C7 cycloalkyl),
(f) xe2x80x94(C1-C6 alkyl)xe2x80x94Oxe2x80x94(C1-C3 alkyl),
(g) xe2x80x94C1-C6 alkenyl with one or two double bonds,
(h) xe2x80x94C1-C6 alkynyl with one or two triple bonds,
(i) xe2x80x94C1-C6 alkyl chain with one double bond and one triple bond,
(j) xe2x80x94R1-aryl where R1-aryl is as defined above, or
(k) xe2x80x94R1-heteroaryl where R1-heteroaryl is as defined above,
(8) xe2x80x94COxe2x80x94(C3-C12 alkyl),
(9) xe2x80x94COxe2x80x94(C3-C6 cycloalkyl),
(10) xe2x80x94COxe2x80x94R1-heteroaryl where R1-heteroaryl is as defined above,
(11) xe2x80x94COxe2x80x94R1-heterocycle where R1-heterocycle is as defined above,
(12) xe2x80x94COxe2x80x94RN-4 where RN-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with one or two C1-C3 alkyl,
(13) xe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is:
(a) C1-C6 alkyl, or
(b) xe2x80x94(CH2)0-2xe2x80x94(R1-aryl) where R1-aryl is as defined above,
(14) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are as defined above,
(15) xe2x80x94SOxe2x80x94(C1-C8 alkyl),
(16) xe2x80x94SO2xe2x80x94(C3-C12 alkyl),
(17) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is as defined above,
(18) xe2x80x94NHxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(19) xe2x80x94Nxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(20) xe2x80x94N(C1-C3 alkyl)-COxe2x80x94RN-5 where RN-5 is as defined above,
(21) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 can be the same or different and are as defined above,
(22) xe2x80x94RN-4 where RN-4 is as defined above,
(23) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(24) xe2x80x94Oxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(25) xe2x80x94Oxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(26) xe2x80x94Oxe2x80x94(C1-C6 alkyl),
(27) xe2x80x94Oxe2x80x94(C2-C5 alkyl)-COOH, or
(28) xe2x80x94Sxe2x80x94(C1-C6 alkyl),
(C) xe2x80x94RN-arylxe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(D) xe2x80x94RN-arylxe2x80x94RN-heteroaryl where xe2x80x94RN-aryl and xe2x80x94RN-heteroaryl are as defined above,
(E) xe2x80x94RN-heteroarylxe2x80x94RN-aryl where xe2x80x94RN-aryl and xe2x80x94RN-heteroaryl are as defined above,
(F) xe2x80x94RN-heteroarylxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(G) xe2x80x94RN-arylxe2x80x94Oxe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(H) xe2x80x94RN-arylxe2x80x94Sxe2x80x94R-Naryl where xe2x80x94RN-aryl is as defined above,
(I) xe2x80x94RN-heteroarylxe2x80x94Oxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(J) xe2x80x94RN-heteroarylxe2x80x94Sxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(K) xe2x80x94RN-arylxe2x80x94COxe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(L) xe2x80x94RN-arylxe2x80x94COxe2x80x94RN-heteroaryl where xe2x80x94RN-aryl and RN-heteroaryl are as defined above,
(M) xe2x80x94RN-arylxe2x80x94SO2xe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(N) xe2x80x94RN-heteroarylxe2x80x94COxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(O) xe2x80x94RN-heteroarylxe2x80x94SO2xe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(P) xe2x80x94RN-arylxe2x80x94Oxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-aryl is as defined above,
(Q) xe2x80x94RN-arylxe2x80x94Sxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-aryl is as defined above,
(R) xe2x80x94RN-heteroarylxe2x80x94Oxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-heteroaryl is as defined above, or
(S) xe2x80x94RN-heteroarylxe2x80x94Sxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-heteroaryl is as defined above,
(II) Axe2x80x94XNxe2x80x94 where XN is xe2x80x94COxe2x80x94,
wherein A is
(A) xe2x80x94Txe2x80x94Exe2x80x94(Q)mxe2x80x2,
(1) where xe2x80x94T is: 
where
(a) x=1 when y=1 and x=2 when y=0,
(b) m is 0, 1, 2 or 3,
(c) the values of x and y vary independently on each carbon when m is 2 and 3, and
(d) Rxe2x80x2xe2x80x3 varies independently on each carbon and is H, (C1-C2) alkyl, phenyl, or phenyl(C1-C3)alkyl;
(2) xe2x80x94E is
(a) C1-C5 alkyl, but only if mxe2x80x2 does not equal 0,
(b) methylthioxy(C2-C4)alkyl,
(c) an aryl group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,
(d) a heterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,
(e) a mono or fused ring cycloalkyl group having 5 to 10 carbon atoms,
(f) biphenyl,
(g) diphenyl ether,
(h) diphenylketone,
(i) phenyl(C1-C8)alkyloxyphenyl, or
(j) C1-C6 alkoxy;
(3) xe2x80x94Q is
(a) C1-C3 alkyl,
(b) C1-C3 alkoxy,
(c) C1-C3 alkylthioxy,
(d) C1-C6 alkylacylamino,
(e) C1-C6 alkylacyloxy,
(f) amido (including primary, C1-C6 alkyl and phenyl secondary and tertiary amino moieties),
(g) C1-C6 alkylamino
(h) phenylamino,
(i) carbamyl (including C1-C6 alkyl and phenyl amides and esters),
(j) carboxyl (including C1-C6 alkyl and phenyl esters),
(k) carboxy(C2-C5)alkoxy,
(l) carboxy(C2-C5)alkylthioxy,
(m) heterocyclylacyl,
(n) heteroarylacyl, or
(o) hydroxyl;
(4) mxe2x80x2 is 0, 1, 2 or 3;
(B) xe2x80x94E(Q)mxe2x80x3 wherein E and xe2x80x94Q are as defined as above and mxe2x80x3 is 0, 1, 2, or 3;
(C) xe2x80x94Txe2x80x94E wherein xe2x80x94E and xe2x80x94Q are as defined as above; or
(D) xe2x80x94E wherein xe2x80x94E is as defined as above;
(III) xe2x80x94COxe2x80x94(C1-C6 alkyl) where alkyl is unsubstituted or substituted with one or two:
(A) xe2x80x94OH,
(B) xe2x80x94C1-C6 alkoxy,
(C) xe2x80x94C1-C6 thioalkoxy,
(D) xe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is xe2x80x94H, C1-C6 alkyl or -xcfx86,
(E) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) xe2x80x94COxe2x80x94RN-4 where RN-4 is as defined above,
(G) xe2x80x94SO2xe2x80x94(C1-C8 alkyl),
(H) xe2x80x94SO2xe2x80x94NRN-2 RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) xe2x80x94NHxe2x80x94COxe2x80x94(C1-C6 alkyl),
(J) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is as defined above,
(K) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) xe2x80x94RN-4 where RN-4 is as defined above,
(M) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(N) xe2x80x94Oxe2x80x94COxe2x80x94NRN-8RN-8 where the RN-8 is the same or different and are as defined above, or
(O) xe2x80x94Oxe2x80x94(C1-C5 alkyl)-COOH,
(IV) xe2x80x94COxe2x80x94(C1-C3 alkyl)xe2x80x94Oxe2x80x94(C1-C3 alkyl) where alkyl is unsubstituted or substituted with one or two
(A) xe2x80x94OH,
(B) xe2x80x94C1-C6 alkoxy,
(C) xe2x80x94C1-C6 thioalkoxy,
(D) xe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is xe2x80x94H, C1-C6 alkyl or -xcfx86,
(E) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) xe2x80x94COxe2x80x94RN4 where RN-4 is as defined above,
(G) xe2x80x94SO2xe2x80x94(C1-C8 alkyl),
(H) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) xe2x80x94NHxe2x80x94COxe2x80x94(C1-C6 alkyl),
(J) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is as defined above,
(K) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) xe2x80x94RN-4 where RN-4 is as defined above,
(M) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(N) xe2x80x94Oxe2x80x94COxe2x80x94NRN-8RN-8 where the RN-8 are the same or different and are as defined above, or
(O) xe2x80x94Oxe2x80x94(C1-C5 alkyl)-COOH,
(V) xe2x80x94COxe2x80x94(C1-C3 alkyl)xe2x80x94Sxe2x80x94(C1-C3 alkyl) where alkyl is unsubstituted or substituted with one or two
(A) xe2x80x94OH,
(B) xe2x80x94C1-C6 alkoxy,
(C) xe2x80x94C1-C6 thioalkoxy,
(D) xe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is xe2x80x94H, C1-C6 alkyl or -xcfx86,
(E) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) xe2x80x94COxe2x80x94RN-4 where RN-4 is as defined above,
(G) xe2x80x94SO2xe2x80x94(C1-C8 alkyl),
(H) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) xe2x80x94NHxe2x80x94COxe2x80x94(C1-C6 alkyl),
(J) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is as defined above,
(K) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) xe2x80x94RN-4 where RN-4 is as defined above,
(M) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(N) xe2x80x94Oxe2x80x94COxe2x80x94NRN-8RN-8 where the RN-8 are the same or different and are as defined above, or
(O) xe2x80x94Oxe2x80x94(C1-C5 alkyl)-COOH,
(VI) xe2x80x94COxe2x80x94CH(xe2x80x94(CH2)0-2xe2x80x94Oxe2x80x94RN-10)xe2x80x94(CH2)0-2xe2x80x94RN-aryl/RN-heteroaryl) where RN-aryl and RN-heteroaryl are as defined above, where RN-10 is:
(A) xe2x80x94H,
(B) C1-C6 alkyl,
(C) C3-C7 cycloalkyl,
(D) C2-C6 alkenyl with one double bond,
(E) C2-C6 alkynyl with one triple bond,
(F) R1-aryl where R1-aryl is as defined above, or
(G) RN-heteroatyl where RN-heteroaryl is as defined above;
xe2x80x83where B is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94N(C1-C6 alkyl)-;
where RC is:
(I) xe2x80x94(C1-C10)alkyl-K1-3 in which:
(A) the alkyl chain is unsubstituted or substituted with one xe2x80x94OH,
(B) the alkyl chain is unsubstituted or substituted with one C1-C6 alkoxy unsubstituted or substituted with 1-5 xe2x80x94F,
(C) the alkyl chain is unsubstituted or substituted with one xe2x80x94O-xcfx86,
(D) the alkyl chain is unsubstituted or substituted with 1-5 xe2x80x94F,
(E) the alkyl chain is unsubstituted or substituted with a combination of up to three atoms of oxygen and sulfur each such atom replacing one carbon,
(F) each K is:
(1) H,
(2) C1-C3 alkyl,
(3) C1-C3 alkoxy,
(4) C1-C3 alkylthioxy,
(5) C1-C6 alkylacylamino,
(6) C1-C6 alkylacyloxy,
(7) amido
(8) C1-C6 alkylamino
(9) phenylamino,
(10) carbamyl
(11) carboxyl
(12) carboxy(C2-C5)alkoxy,
(13) carboxy(C2-C5)alkylthioxy,
(14) heterocyclylacyl,
(15) heteroarylacyl,
(16) amino unsubstituted or substituted with C1-C6 alkyl,
(17) hydroxyl, or
(18) carboxyl methyl ester;
(II) xe2x80x94(CH2)0-3xe2x80x94Jxe2x80x94[(xe2x80x94(CH2)0-3xe2x80x94K]1-3 where K is as defined above and J is:
(A) a 5 to 7 atom monocyclic aryl group,
(B) a 8 to 12 atom multicyclic aryl group,
(C) a 5 to 7 atom heterocyclic group,
(D) a 8 to 12 atom multicyclic heterocyclic group, or
(E) a 5 to 10 atom monocyclic or multicyclic cycloalkyl group;
(III) xe2x80x94(CH2)0-3xe2x80x94(C3-C7) cycloalkyl where cycloalkyl can be unsubstituted or substituted with one, two or three
(A) C1-C3 alkyl unsubstituted or substituted with 1, 2, 3, or 4 xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(B) xe2x80x94COxe2x80x94OH,
(C) xe2x80x94COxe2x80x94Oxe2x80x94(C1-C4 alkyl),
(D) xe2x80x94OH, or
(E) C1-C6 alkoxy,
(IV) xe2x80x94(CH2)2-6xe2x80x94OH,
(V) xe2x80x94(CRC-xRC-y)0-4xe2x80x94RC-aryl where RC-x and RC-y are xe2x80x94H, C1-C4 alkyl and xcfx86- and RC-aryl is the same as RN-aryl,
(VI) (CH2)0-4xe2x80x94RC-heteroaryl where RC-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) isoxazolyl,
(Q) pyrazolyl,
(R) indolizinyl,
(S) indazolyl,
(T) benzothiazolyl,
(U) benzimidazolyl,
(V) benzofuranyl,
(W) furanyl,
(X) thienyl,
(Y) pyrrolyl,
(Z) oxadiazolyl,
(AA) thiadiazolyl,
(BB) triazolyl,
(CC) tetrazolyl,
(DD) 1,4-benzodioxan
(EE) purinyl,
(FF) oxazolopyridinyl,
(GG) imidazopyridinyl,
(HH) isothiazolyl,
(II) naphthyridinyl,
(JJ) cinnolinyl,
(KK) carbazolyl,
(LL) xcex2-carbolinyl,
(MM) isochromanyl,
(NN) chromanyl,
(OO) furazanyl,
(PP) tetrahydroisoquinoline,
(QQ) isoindolinyl,
(RR) isobenzotetrahydrofuranyl,
(SS) isobenzotetrahydrothienyl,
(TT) isobenzothiophenyl,
(UU) benzoxazolyl, or
(VV) pyridopyridinyl,
(VII) xe2x80x94(CH2)0-4xe2x80x94RC-heterocycle where RC-heterocycle is the same as R1-heterocycle, 
(VIII) xe2x80x94C(RC-1)(RC-2)xe2x80x94COxe2x80x94NHxe2x80x94RC-3 where RC-1 and RC-2 are the same or different and are:
(A) xe2x80x94H,
(B) xe2x80x94C1-C6 alkyl,
(C) xe2x80x94(C1-C4 alkyl)-RC-aryl where RC-aryl is as defined above for R1-aryl,
(D) xe2x80x94(C1-C4 alkyl)-RC-heteroaryl where RC-heteroaryl is as defined above,
(E) xe2x80x94(C1-C4 alkyl)-RC-heterocycle where RC-heterocycle is as defined above,
(F) xe2x80x94RC-heteroaryl where RC-heteroaryl is as defined above,
(G) xe2x80x94RC-heterocycle where RC-heterocycle is as defined above,
(H) xe2x80x94(CH2)1-4xe2x80x94OH,
(I) xe2x80x94(CH2)1-4xe2x80x94RC-4xe2x80x94(CH2)1-4xe2x80x94RCxe2x80x2-aryl where RC-4 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94or xe2x80x94NHRC-5xe2x80x94 where RC-5 is C1-C6 alkyl, and where RCxe2x80x2-aryl is as defined above,
(J) xe2x80x94(CH2)1-4xe2x80x94RC-4xe2x80x94(CH2)1-4xe2x80x94RC-heteroaryl where RC-4 and RC-heteroaryl are as defined above, or
(K) xe2x80x94RCxe2x80x2-aryl where RCxe2x80x2-aryl is as defined above,
and where RC-3 is:
(A) xe2x80x94H,
(B) xe2x80x94C1-C6 alkyl,
(C) xe2x80x94RCxe2x80x2-aryl where RCxe2x80x2-aryl is as defined above,
(D) xe2x80x94RC-heteroaryl where RC-heteroaryl is as defined above,
(E) xe2x80x94RC-heterocycle where RC-heterocycle is as defined above,
(F) xe2x80x94(C1-C4 alkyl)-RCxe2x80x2-aryl where RCxe2x80x2-aryl is as defined above,
(G) xe2x80x94(C1-C4 alkyl)-RC-heteroaryl where RC-heteroaryl is as defined above, or
(H) xe2x80x94(C1-C4 alkyl)-RC-heterocycle where RC-heterocycle is as defined above,
(IX) xe2x80x94CH(xcfx86)2,
(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring where heteroaryl is as defined above and phenyl and heteroaryl are unsubstituted or substituted with one, two or three:
(A) C1-C3 alkyl,
(B) xe2x80x94CF3,
(C) xe2x80x94F, Cl, xe2x80x94Br and xe2x80x94I,
(D) C1-C3 alkoxy,
(E) xe2x80x94OCF3,
(F) xe2x80x94NH2,
(G) xe2x80x94OH, or
(H) xe2x80x94Cxe2x89xa1N,
(XI) xe2x80x94CH2xe2x80x94Cxe2x89xa1xe2x80x94CH;
(XII) xe2x80x94(CH2)0-1xe2x80x94CHRC-5xe2x80x94(CH2)0-1-xcfx86 where RC-5 is:
(A) xe2x80x94OH, or
(B)xe2x80x94CH2xe2x80x94OH;
(XIII) xe2x80x94CH(-xcfx86)-COxe2x80x94O(C1-C3 alkyl);
(XIV) xe2x80x94CH(xe2x80x94CH2xe2x80x94OH)xe2x80x94CH(xe2x80x94OH)-xcfx86- NO2;
(XV) xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94OH;
(XVI) xe2x80x94CH2xe2x80x94NHxe2x80x94CH2xe2x80x94CH(xe2x80x94Oxe2x80x94CH2xe2x80x94CH3)2;
(XVII) xe2x80x94(C2-C8) alkynyl; or
(XVIII) xe2x80x94H; or a pharmaceutically acceptable salt thereof.
Additionally disclosed are compounds of the formula 
where R1 is:
(V) xe2x80x94CH2-phenyl, where phenyl is substituted with two xe2x80x94F in the 3xe2x80x94 and 5-positions giving 3,5-difluorophenyl, or
(VI) xe2x80x94(CH2)n1xe2x80x94(R1-heteroaryl), where n1 and R1-heteroaryl are as defined above; and
PROTECTING GROUP is t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl, isobornyloxycarbonyl, -phenyl-C(xe2x95x90N)xe2x80x94H, or 1-piperidyloxycarbonyl.
Additionally disclosed are epoxide compounds of the formula: 
where R1 is:
(A) xe2x80x94CH2-xcfx86 where -xcfx86 is substituted with two xe2x80x94F,
(B) xe2x80x94(CH2)n1xe2x80x94Rheteroaryl where n1 is 0, 1, 2, or 3 and R1-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) imidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) xcex2-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrothienyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
(C)xe2x80x94(CH2)n1xe2x80x94R1-heterocycle where n1 is 0, 1, 2, or 3 and R1-heterocycle is:
(A) morpholinyl,
(B) thiomorpholinyl,
(C) thiomorpholinyl S-oxide,
(D) thiomorpholinyl S,S-dioxide,
(E) piperazinyl,
(F) homopiperazinyl,
(G) pyrrolidinyl,
(H) pyrrolinyl,
(I) tetrahydropyranyl,
(J) piperidinyl,
(K) tetrahydrofuranyl, or
(L) tetrahydrothiophenyl, and
PROTECTING GROUP is t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl, isobornyloxycarbonyl, -phenyl-C(xe2x95x90N)xe2x80x94H, or 1-piperidyloxycarbonyl.
Additionally disclosed are compounds of the formula: 
where R1 is:
(V) xe2x80x94CH2-phenyl, where phenyl is substituted with two xe2x80x94F in the 3xe2x80x94 and 5-positions giving 3,5-difluorophenyl, or
(VI) (CH2)n1xe2x80x94(R1-heteroaryl), where n1 and R1-heteroaryl are as defined above; where R2 is as defined in claim 1; and
PROTECTING GROUP is t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl, isobomyloxycarbonyl, -phenyl-C(xe2x95x90N)xe2x80x94H, or 1-piperidyloxycarbonyl.
Additionally disclosed are amine compounds of the formula: 
where R1 is:
(V) xe2x80x94CH2-phenyl, where phenyl is substituted with two xe2x80x94F in the 3xe2x80x94 and 5-positions giving 3,5-difluorophenyl, or
(VI) xe2x80x94(CH2)n1xe2x80x94(R1-heteroaryl), where n1 and R1-heteroaryl are as defined above; and
where R2 is as defined in claim 1.
Additionally disclosed are lactone compounds of the formula: 
where R1 is:
(I) C1-C6 alkyl, unsubstituted or substituted with one, two or three C1-C3 alkyl, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94OH, xe2x80x94NH2, xe2x80x94Cxe2x89xa1N, xe2x80x94CF3, or xe2x80x94N3,
(II) xe2x80x94(CH2)1-2xe2x80x94Sxe2x80x94CH3,
(III) xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94CH3,
(IV) xe2x80x94CH2xe2x80x94(C2-C6 alkenyl) unsubstituted or substituted by one xe2x80x94F,
(V) xe2x80x94(CH2)0-3xe2x80x94(R1-aryl) where R1-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinyl unsubstituted or substituted on the aryl ring with one or two of the following substituents which can be the same or different:
(A) C1-C3 alyl,
(B) xe2x80x94CF3,
(C) xe2x80x94F, Cl, xe2x80x94Br and xe2x80x94I,
(D) C1-C3 alkoxy,
(E) xe2x80x94Oxe2x80x94CF3,
(F) xe2x80x94NH2,
(G) xe2x80x94OH, or
(H)xe2x80x94Cxe2x89xa1N,
(VI) xe2x80x94(CH2)n1xe2x80x94(R1-heteroaryl) where n1 is 0, 1,2, or 3 and R1-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) imidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) xcex2-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrothienyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
xe2x80x83where the R1-heteroaryl group is bonded to xe2x80x94(CH2)0-3xe2x80x94 by any ring atom of the parent RN-heteroaryl group substituted by hydrogen such that the new bond to the R1-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is unsubstituted or substituted with one or two:
(1) C1-C3 alkyl,
(2) CF3,
(3) xe2x80x94F, Cl, xe2x80x94Br, or xe2x80x94I,
(4) C1-C3 alkoxy,
(5) xe2x80x94Oxe2x80x94CF3,
(6) xe2x80x94NH2,
(7) xe2x80x94OH, or
(8) xe2x80x94Cxe2x89xa1N,
xe2x80x83with the proviso that when n1 is zero R1-heteroaryl is not bonded to the carbon chain by nitrogen, or
(VII) (CH2)n1xe2x80x94(R1-heterocycle) where n1 is as defined above and R1-heterocycle is:
(A) morpholinyl,
(B) thiomorpholinyl,
(C) thiomorpholinyl S-oxide,
(D) thiomorpholinyl S,S-dioxide,
(E) piperazinyl,
(F) homopiperazinyl,
(G) pyrrolidinyl,
(H) pyrrolinyl,
(I) tetrahydropyranyl,
(J) piperidinyl,
(K) tetrahydrofuranyl, or
(L) tetrahydrothiophenyl,
xe2x80x83where the R1-heterocycle group is bonded by any atom of the parent R1-heterocycle group substituted by hydrogen such that the new bond to the R1-heteroaryl group replaces the hydrogen atom and its bond, where heterocycle is unsubstituted or substituted with one or two:
(1) xe2x95x90O,
(2) C1-C3 alkyl,
(3) xe2x80x94CF3,
(4) xe2x80x94F, Cl, xe2x80x94Br and xe2x80x94I,
(5) C1-C3 alkoxy,
(6) xe2x80x94Oxe2x80x94CF3,
(7) xe2x80x94NH2,
(8) xe2x80x94OH, or
(9) xe2x80x94CN,
xe2x80x83with the proviso that when n, is zero R1-heterocycle is not bonded to the carbon chain by nitrogen;
where R2 is:
(I) xe2x80x94H
(II) C1-C6 alkyl, or
(III) xe2x80x94(CH2)0-4xe2x80x94R2-1 where R2-1 is (C3-C6)cycloalkyl, R1-aryl or R1-heteroaryl where R1-aryl and R1-heteroaryl are as defined above,
where RN is:
(I) RN-1xe2x80x94XNxe2x80x94 where XN is:
(A) xe2x80x94COxe2x80x94,
(B) xe2x80x94SO2xe2x80x94,
(C) xe2x80x94(CRxe2x80x2Rxe2x80x3)1-6 where Rxe2x80x2 and Rxe2x80x3 are the same or different and are xe2x80x94H or C1-C4 alkyl,
(D) xe2x80x94COxe2x80x94(CRxe2x80x2Rxe2x80x3)1-6xe2x80x94XN-1 where XN-1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94NRxe2x80x2Rxe2x80x3xe2x80x94 and where Rxe2x80x2 and Rxe2x80x3 are as defined above,
(E) a single bond;
where RN-1 is:
(A) RN-aryl where RN-aryl is phenyl, 1-naphthyl and 2-naphthyl unsubstituted or substituted with one, two, three or four of the following substituents which can be the same or different and are:
(1) C1-C6 alkyl,
(2) xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(3) xe2x80x94OH,
(4) xe2x80x94NO2,
(5) xe2x80x94COxe2x80x94OH,
(6) xe2x80x94Cxe2x89xa1N,
(7) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are:
(a) xe2x80x94H,
(b) xe2x80x94C1-C6 alkyl unsubstituted or substituted with one
(i) xe2x80x94OH, or
(ii) xe2x80x94NH2,
(c) xe2x80x94C1-C6 alkyl unsubstituted or substituted with one to three xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(d) xe2x80x94C3-C7 cycloalkyl,
(e) xe2x80x94(C1-C2 alkyl)xe2x80x94(C3-C7 cycloalkyl),
(f) xe2x80x94(C1-C6 alkyl)xe2x80x94Oxe2x80x94(C1-C3 alkyl),
(g) xe2x80x94C1-C6 alkenyl with one or two double bonds,
(h) xe2x80x94C1-C6 alkynyl with one or two triple bonds,
(i) xe2x80x94C1-C6 alkyl chain with one double bond and one triple bond,
(j) xe2x80x94R1-aryl where R1-aryl is as defined above, or
(k) R1-heteroaryl where R1-heteroaryl is as defined above,
(8) xe2x80x94COxe2x80x94(C3-C12 alkyl),
(9) xe2x80x94COxe2x80x94(C3-C6 cycloalkyl),
(10) xe2x80x94COxe2x80x94R1-heteroaryl where R1-heteroaryl is as defined above,
(11) xe2x80x94COxe2x80x94R1-heterocycle where R1-heterocycle is as defined above,
(12) xe2x80x94COxe2x80x94RN-4 where RN-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with one or two C1-C3 alkyl,
(13) xe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is:
(a) C1-C6 alkyl, or
(b) (CH2)0-2xe2x80x94(R1-aryl) where R1-aryl is as defined above,
(14) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are as defined above,
(15) xe2x80x94SOxe2x80x94(C1-C8 alkyl),
(16) xe2x80x94SO2xe2x80x94(C3-C12 alkyl),
(17) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is as defined above,
(18) xe2x80x94NHxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(19) xe2x80x94Nxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(20) xe2x80x94N(C1-C3 alkyl)-COxe2x80x94RN-5 where RN-5 is as defined above,
(21) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 can be the same or different and are as defined above,
(22) xe2x80x94RN-4 where RN-4 is as defined above,
(23) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(24) xe2x80x94Oxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(25) xe2x80x94Oxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(26) xe2x80x94Oxe2x80x94(C1-C6 alkyl),
(27) xe2x80x94Oxe2x80x94(C2-C5 alkyl)-COOH,
(28) xe2x80x94Sxe2x80x94(C1-C6 alkyl),
(29) C1-C6 alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 xe2x80x94F,
(30) xe2x80x94Oxe2x80x94(C1-C6 alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 xe2x80x94F, or
(31) xe2x80x94O-xcfx86,
(B) xe2x80x94RN-heteroaryl where RN-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) imidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) xcex2-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrothienyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
xe2x80x83where the RN-heteroaryl group is bonded by any atom of the parent RN-heteroaryl group substituted by hydrogen such that the new bond to the RN-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is unsubstituted or substituted with one or two:
(1) C1-C6 alkyl,
(2) xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(3) xe2x80x94OH,
(4) xe2x80x94NO2,
(5) xe2x80x94COxe2x80x94OH,
(6) xe2x80x94Cxe2x89xa1N,
(7) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are:
(a) xe2x80x94H,
(b) xe2x80x94C1-C6 alkyl unsubstituted or substituted with one
(i) xe2x80x94OH, or
(ii) xe2x80x94NH2,
(c) xe2x80x94C1-C6 alkyl unsubstituted or substituted with 1, 2, or 3 xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(d) xe2x80x94C3-C7 cycloalkyl,
(e) xe2x80x94(C1-C2 alkyl)xe2x80x94(C3-C7 cycloalkyl),
(f) xe2x80x94(C1-C6 alkyl)xe2x80x94Oxe2x80x94(C1-C3 alkyl),
(g) xe2x80x94C1-C6 alkenyl with one or two double bonds,
(h) xe2x80x94C1-C6 alkynyl with one or two triple bonds,
(i) xe2x80x94C1-C6 alkyl chain with one double bond and one triple bond,
(j) xe2x80x94R1-aryl where R1-aryl is as defined above, or
(k) xe2x80x94R1-heteroaryl where R1-heteroaryl is as defined above,
(8) xe2x80x94COxe2x80x94(C3-C12 alkyl),
(9) xe2x80x94COxe2x80x94(C3-C6 cycloalkyl),
(10) xe2x80x94COxe2x80x94R1-heteroaryl where R1-heteroaryl is as defined above,
(11) xe2x80x94COxe2x80x94R1-heterocycle where R1-heterocycle is as defined above,
(12) xe2x80x94COxe2x80x94RN-4 where RN-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with one or two C1-C3 alkyl,
(13) xe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is:
(a) C1-C6 alkyl, or
(b) xe2x80x94(CH2)0-2xe2x80x94(R1-aryl) where R1-aryl is as defined above,
(14) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are as defined above,
(15) xe2x80x94SOxe2x80x94(C1-C8 alkyl),
(16) xe2x80x94SO2xe2x80x94(C3-C12 alkyl),
(17) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is as defined above,
(18) xe2x80x94NHxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(19) xe2x80x94Nxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(20) xe2x80x94N(C1-C3 alkyl)-COxe2x80x94RN-5 where RN-5 is as defined above,
(21) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 can be the same or different and are as defined above,
(22) xe2x80x94RN-4 where RN-4 is as defined above,
(23) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(24) xe2x80x94Oxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(25) xe2x80x94Oxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(26) xe2x80x94Oxe2x80x94(C1-C6 alkyl),
(27) xe2x80x94Oxe2x80x94(C2-C5 alkyl)-COOH, or
(28) xe2x80x94Sxe2x80x94(C1-C6 alkyl),
(C) xe2x80x94RN-arylxe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(D) xe2x80x94RN-arylxe2x80x94RN-heteroaryl where xe2x80x94RN-aryl and xe2x80x94RN-heteroaryl are as defined above,
(E) xe2x80x94RN-heteroaryl RN-aryl where xe2x80x94RN-aryl and xe2x80x94RN-heteroaryl are as defined above,
(F) RN-heteroarylxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(G) xe2x80x94RN-arylxe2x80x94Oxe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(H) xe2x80x94RN-arylxe2x80x94Sxe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(I) xe2x80x94RN-heteroarylxe2x80x94Oxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(J) xe2x80x94RN-heteroarylxe2x80x94Sxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(K) xe2x80x94RN-arylCOxe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(L) xe2x80x94RN-arylxe2x80x94COxe2x80x94RN-heteroaryl where xe2x80x94RN-aryl and RN-heteroaryl are as defined above,
(M) xe2x80x94RN-arylxe2x80x94SO2xe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(N) xe2x80x94RN-heteroarylxe2x80x94COxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(O) xe2x80x94RN-heteroarylxe2x80x94SO2xe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(P) xe2x80x94RN-arylxe2x80x94Oxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-aryl is as defined above,
(Q) xe2x80x94RN-arylxe2x80x94Sxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-aryl is as defined above,
(R) xe2x80x94RN-heteroarylxe2x80x94Oxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-heteroaryl is as defined above, or
(S) xe2x80x94RN-heteroarylxe2x80x94Sxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-heteroaryl is as defined above,
(II) Axe2x80x94XNxe2x80x94 where XN is xe2x80x94COxe2x80x94,
wherein A is
(A) xe2x80x94Txe2x80x94Exe2x80x94(Q)mxe2x80x2,
(1) where xe2x80x94T is: 
xe2x80x83where
(a) x=1 when y=1 and x=2 when y=0,
(b) m is 0, 1, 2 or 3,
(c) the values of x and y vary independently on each carbon when m is 2 and 3, and
(d) Rxe2x80x2xe2x80x3 varies independently on each carbon and is H, (C1-C2) alkyl, phenyl, or phenyl(C1-C3)alkyl;
(2) xe2x80x94E is
(a) C1-C5 alkyl, but only if mxe2x80x2 does not equal 0,
(b) methylthioxy(C2-C4)alkyl,
(c) an aryl group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,
(d) a heterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,
(e) a mono or fused ring cycloalkyl group having 5 to 10 carbon atoms,
(f) biphenyl,
(g) diphenyl ether,
(h) diphenylketone,
(i) phenyl(C1-C8)alkyloxyphenyl, or
(j) C1-C6 alkoxy;
(3) xe2x80x94Q is
(a) C1-C3 alkyl,
(b) C1-C3 alkoxy,
(c) C1-C3 alkylthioxy,
(d) C1-C6 alkylacylamino,
(e) C1-C6 alkylacyloxy,
(f) amido (including primary, C1-C6 alkyl and phenyl secondary and tertiary amino moieties),
(g) C1-C6 alkylamino
(h) phenylamino,
(i) carbamyl (including C1-C6 alkyl and phenyl amides and esters),
(j) carboxyl (including C1-C6 alkyl and phenyl esters),
(k) carboxy(C2-C5)alkoxy,
(l) carboxy(C2-C5)alkylthioxy,
(m) heterocyclylacyl,
(n) heteroarylacyl, or
(o) hydroxyl;
(4) mxe2x80x2 is 0, 1, 2 or 3;
(B) xe2x80x94E(Q)mxe2x80x3 wherein E and xe2x80x94Q are as defined as above and mxe2x80x3 is 0, 1, 2, or 3;
(C) xe2x80x94Txe2x80x94E wherein xe2x80x94E and xe2x80x94Q are as defined as above; or
(D) xe2x80x94E wherein xe2x80x94E is as defined as above;
(III) xe2x80x94COxe2x80x94(C1-C6 alkyl) where alkyl is unsubstituted or substituted with one or two:
(A) xe2x80x94OH,
(B) xe2x80x94C1-C6 alkoxy,
(C) xe2x80x94C1-C6 thioalkoxy,
(D) xe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is xe2x80x94H, C1-C6 alkyl or -xcfx86,
(E) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) xe2x80x94COxe2x80x94RN-4 where RN-4 is as defined above,
(G) xe2x80x94SO2xe2x80x94(C1-C8 alkyl),
(H) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) xe2x80x94NHxe2x80x94COxe2x80x94(C1-C6 alkyl),
(J) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is as defined above,
(K) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) xe2x80x94RN-4 where RN-4 is as defined above,
(M) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(N) xe2x80x94Oxe2x80x94COxe2x80x94NRN-8RN-8 where the RN-8 is the same or different and are as defined above, or
(O) xe2x80x94Oxe2x80x94(C1-C5 alkyl)-COOH,
(IV) xe2x80x94COxe2x80x94(C1-C3 alkyl)xe2x80x94Oxe2x80x94(C1-C3 alkyl) where alkyl is unsubstituted or substituted with one or two
(A) xe2x80x94OH,
(B) xe2x80x94C1-C6 alkoxy,
(C) xe2x80x94C1-C6 thioalkoxy,
(D) xe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is xe2x80x94H, C1-C6 alkyl or -xcfx86,
(E) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) xe2x80x94COxe2x80x94RN-4 where RN-4 is as defined above,
(G) xe2x80x94SO2xe2x80x94(C1-C8 alkyl),
(H) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) xe2x80x94NHxe2x80x94COxe2x80x94(C1-C6 alkyl),
(J) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is as defined above,
(K) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) xe2x80x94RN-4 where RN-4 is as defined above,
(M) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(N) xe2x80x94Oxe2x80x94COxe2x80x94NRN-8RN-8 where the RN-8 are the same or different and are as defined above, or
(O) xe2x80x94Oxe2x80x94(C1-C5 alkyl)-COOH,
(V) xe2x80x94COxe2x80x94(C1-C3 alkyl)xe2x80x94Sxe2x80x94(C1-C3 alkyl) where alkyl is unsubstituted or substituted with one or two
(A) xe2x80x94OH,
(B) xe2x80x94C1-C6 alkoxy,
(C) xe2x80x94C1-C6 thioalkoxy,
(D) xe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is xe2x80x94H, C1-C6 alkyl or -xcfx86,
(E) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) xe2x80x94COxe2x80x94RN-4 where RN-4 is as defined above,
(G) xe2x80x94SO2xe2x80x94(C1-C8 alkyl),
(H) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) xe2x80x94NHxe2x80x94COxe2x80x94(C1-C6 alkyl),
(J) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is as defined above,
(K) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) xe2x80x94RN-4 where RN-4 is as defined above,
(M) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(N) xe2x80x94Oxe2x80x94COxe2x80x94NRN-8RN-8 where the RN-8 are the same or different and are as defined above, or
(O) xe2x80x94Oxe2x80x94(C1-C5 alkyl)-COOH,
(VI)xe2x80x94COxe2x80x94CH(xe2x80x94(CH2)0-2xe2x80x94Oxe2x80x94RN-10)xe2x80x94(CH2)0-2xe2x80x94RN-aryl/RN-heteroaryl) where RN-aryl and RN-heteroaryl are as defined above, where RN-10 is:
(A) xe2x80x94H,
(B) C1-C6 alkyl,
(C) C3-C7 cycloalkyl,
(D) C2-C6 alkenyl with one double bond,
(E) C2-C6 alkynyl with one triple bond,
(F) R1-aryl where R1-aryl is as defined above, or
(G) RN-heteroaryl where RN-heteroaryl is as defined above.
Disclosed is a method of treating a patient who has, or in preventing a patient from getting, a disease or condition selected from Alzheimer""s disease, mild cognitive impairment, Down""s syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy body type of Alzheimer""s disease or central or peripheral amyloid diseases and who is in need of such treatment which comprises administration of a therapeutically effective amount of a hydroxyethylene compound of formula (XII): 
where R1 is:
(I) C1-C6 alkyl, unsubstituted or substituted with one, two or three C1-C3 alkyl, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94OH, xe2x80x94NH2, xe2x80x94Cxe2x89xa1N, xe2x80x94CF3, or xe2x80x94N3,
(II) xe2x80x94(CH2)1-2xe2x80x94Sxe2x80x94CH3,
(III) xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94CH3,
(IV) xe2x80x94CH2xe2x80x94(C2-C6 alkenyl) unsubstituted or substituted by one xe2x80x94F,
(V) xe2x80x94(CH2)0-3xe2x80x94(R1-aryl) where R1-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinyl unsubstituted or substituted on the aryl ring with one or two of the following substituents which can be the same or different:
(A) C1-C3 alkyl,
(B) xe2x80x94CF3,
(C) xe2x80x94F, Cl, xe2x80x94Br and xe2x80x94I,
(D) C1-C3 alkoxy,
(E) xe2x80x94Oxe2x80x94CF3,
(F) xe2x80x94NH2,
(G) xe2x80x94OH, or
(H) xe2x80x94Cxe2x80x94N,
(VI) xe2x80x94(CH2)n1xe2x80x94(R1-heteroaryl) where n1 is 0, 1, 2, or 3 and R1-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) imidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) xcex2-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrothienyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
xe2x80x83where the R1-heteroaryl group is bonded to xe2x80x94(CH2)0-3xe2x80x94 by any ring atom of the parent RN-heteroaryl group substituted by hydrogen such that the new bond to the R1-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is unsubstituted or substituted with one or two:
(1) C1-C3 alkyl,
(2)xe2x80x94CF3,
(3) xe2x80x94F, Cl, xe2x80x94Br, or xe2x80x94I,
(4) C1-C3 alkoxy,
(5) xe2x80x94Oxe2x80x94CF3,
(6) xe2x80x94NH2,
(7) xe2x80x94OH, or
(8) xe2x80x94Cxe2x89xa1N,
xe2x80x83with the proviso that when n1 is zero R1-heteroaryl is not bonded to the carbon chain by nitrogen, or
(VII) xe2x80x94(CH2)n1xe2x80x94(R1-heterocycle) where n1 is as defined above and R1-heterocycle is:
(A) morpholinyl,
(B) thiomorpholinyl,
(C) thiomorpholinyl S-oxide,
(D) thiomorpholinyl S,S-dioxide,
(E) piperazinyl,
(F) homopiperazinyl,
(G) pyrrolidinyl,
(H) pyrrolinyl,
(I) tetrahydropyranyl,
(J) piperidinyl,
(K) tetrahydrofuranyl, or
(L) tetrahydrothiophenyl,
xe2x80x83where the R1-heterocycle group is bonded by any atom of the parent R1-heterocycle group substituted by hydrogen such that the new bond to the R1-heteroaryl group replaces the hydrogen atom and its bond, where heterocycle is unsubstituted or substituted with one or two:
(1) xe2x95x90O,
(2) C1-C3 alkyl,
(3) CF3,
(4) xe2x80x94F, Cl, xe2x80x94Br and xe2x80x94I,
(5) C1-C3 alkoxy,
(6) xe2x80x94Oxe2x80x94CF3,
(7) xe2x80x94NH2,
(8) xe2x80x94OH, or
(9) xe2x80x94Cxe2x89xa1N,
xe2x80x83with the proviso that when n1 is zero R1-heterocycle  is not bonded to the carbon chain by nitrogen;
where R2 is:
(I) xe2x80x94H,
(II) C1-C6 alkyl, or
(III) xe2x80x94(CH2)0-4xe2x80x94R2-1 where R21 is (C3-C6)cycloalkyl, R1-aryl or R1-heteroaryl where R1-aryl and R1-heteroaryl are as defined above,
where RN is:
(I) RN-1xe2x80x94XNxe2x80x94 where XN is:
(A) xe2x80x94COxe2x80x94,
(B) xe2x80x94SO2xe2x80x94,
(C) xe2x80x94(CRxe2x80x2Rxe2x80x3)1-6 where Rxe2x80x2 and Rxe2x80x3 are the same or different and are xe2x80x94H or C1-C4 alkyl,
(D) xe2x80x94COxe2x80x94(CRxe2x80x2Rxe2x80x3)1-6xe2x80x94XN-1 where XN-1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94NRxe2x80x2Rxe2x80x3xe2x80x94 and where Rxe2x80x2 and Rxe2x80x3 are as defined above,
(E) a single bond;
where RN-1 is:
(A) RN-aryl where RN-aryl is phenyl, 1-naphthyl and 2-naphthyl unsubstituted or substituted with one, two, three or four of the following substituents which can be the same or different and are:
(1) C1-C6 alkyl
(2) xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(3) xe2x80x94OH,
(4) xe2x80x94NO2,
(5) xe2x80x94COxe2x80x94OH,
(6) xe2x80x94Cxe2x89xa1N,
(7) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are:
(a) xe2x80x94H,
(b) xe2x80x94C1-C6 alkyl unsubstituted or substituted with one
(i) xe2x80x94OH, or
(ii) xe2x80x94NH2,
(c) xe2x80x94C1-C6 alkyl unsubstituted or substituted with one to three xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(d) xe2x80x94C3-C7 cycloalkyl,
(e) xe2x80x94(C1-C2 alkyl)xe2x80x94(C3-C7 cycloalkyl),
(f) xe2x80x94(C1-C6 alkyl)xe2x80x94Oxe2x80x94(C1-C3 alkyl),
(g) xe2x80x94C1-C6 alkenyl with one or two double bonds,
(h) xe2x80x94C1-C6 alkynyl with one or two triple bonds,
(i) xe2x80x94C1-C6 alkyl chain with one double bond and one triple bond,
(j) xe2x80x94R1-aryl where R1-aryl is as defined above, or
(k) R1-heteroaryl where R1-heteroaryl is as defined above,
(8) xe2x80x94COxe2x80x94(C3-C12 alkyl),
(9) xe2x80x94COxe2x80x94(C3-C6 cycloalkyl),
(10) xe2x80x94COxe2x80x94R1-heteroaryl where R1-heteroaryl is as defined above,
(11) xe2x80x94COxe2x80x94R1-heterocycle where R1-heterocycle is as defined above,
(12) xe2x80x94COxe2x80x94RN-4 where RN-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with one or two C1-C3 alkyl,
(13) xe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is:
(a) C1-C6 alkyl, or
(b) xe2x80x94(CH2)0-2xe2x80x94(R1-aryl) where R1-aryl is as defined above,
(14) xe2x80x94SO2-NRN-2RN-3 where RN-2 and RN-3 are as defined above,
(15) xe2x80x94SOxe2x80x94(C1-C8 alkyl),
(16) xe2x80x94SO2xe2x80x94(C3-C12 alkyl),
(17) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is as defined above,
(18) xe2x80x94NHxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(19) xe2x80x94Nxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(20) xe2x80x94N(C1-C3 alkyl)-COxe2x80x94RN-5 where RN-5 is as defined above,
(21) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 can be the same or different and are as defined above,
(22) xe2x80x94RN-4 where RN-4 is as defined above,
(23) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(24) xe2x80x94Oxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(25) xe2x80x94Oxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(26) xe2x80x94Oxe2x80x94(C1-C6 alkyl),
(27) xe2x80x94Oxe2x80x94(C2-C5 alkyl)-COOH,
(28) xe2x80x94Sxe2x80x94(C1-C6 alkyl),
(29) C1-C6 alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 xe2x80x94F,
(30) xe2x80x94Oxe2x80x94(C1-C6 alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5xe2x80x94F, or
(31) xe2x80x94O-xcfx86,
(B) xe2x80x94RN-heteroaryl where RN-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) imidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) xcex2-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrothienyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
xe2x80x83where the RN-heteroaryl group is bonded by any atom of the parent RN-heteroaryl group substituted by hydrogen such that the new bond to the RN-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is unsubstituted or substituted with one or two:
(1) C1-C6 alkyl,
(2) xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(3) xe2x80x94OH,
(4) xe2x80x94NO2,
(5) xe2x80x94COxe2x80x94OH,
(6) xe2x80x94Cxe2x89xa1N,
(7) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are:
(a) xe2x80x94H,
(b) xe2x80x94C1-C6 alkyl unsubstituted or substituted with one
(i) xe2x80x94OH, or
(ii) xe2x80x94NH2,
(c) xe2x80x94C1-C6 alkyl unsubstituted or substituted with 1, 2, or 3 xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(d) xe2x80x94C3-C7 cycloalkyl,
(e) xe2x80x94(C1-C2 alkyl)xe2x80x94(C3-C7 cycloalkyl),
(f) xe2x80x94(C1-C6 alkyl)xe2x80x94Oxe2x80x94(C1-C3 alkyl),
(g) xe2x80x94C1-C6 alkenyl with one or two double bonds,
(h) xe2x80x94C1-C6 alkynyl with one or two triple bonds,
(i) xe2x80x94C1-C6 alkyl chain with one double bond and one triple bond,
(j) xe2x80x94R1-aryl where R1-aryl is as defined above, or
(k) xe2x80x94R1-heteroaryl where R1-heteroaryl is as defined above,
(8) xe2x80x94COxe2x80x94(C3-C12 alkyl),
(9) xe2x80x94COxe2x80x94(C3-C6 cycloalkyl),
(10) xe2x80x94COxe2x80x94R1-heteroaryl where R1-heteroaryl is as defined above,
(11) xe2x80x94COxe2x80x94R1-heterocycle where R1-heterocycle is as defined above,
(12) xe2x80x94COxe2x80x94RN-4 where RN-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with one or two C1-C3 alkyl,
(13) xe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is:
(a) C1-C6 alkyl, or
(b) xe2x80x94(CH2)0-2xe2x80x94(R1-aryl) where R1-aryl is as defined above,
(14) xe2x80x94SO2xe2x80x94NRN-2 RN-3 where RN-2 and RN-3 are as defined above,
(15) xe2x80x94SOxe2x80x94(C1-C8 alkyl),
(16) xe2x80x94SO2xe2x80x94(C3-C12 alkyl),
(17) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is as defined above,
(18) xe2x80x94NHxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(19) xe2x80x94Nxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(20) xe2x80x94N(C1-C3 alkyl)-COxe2x80x94RN-5 where RN-5 is as defined above,
(21) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 can be the same or different and are as defined above,
(22) xe2x80x94RN-4 where RN-4 is as defined above,
(23) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(24) xe2x80x94Oxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(25) xe2x80x94Oxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(26) xe2x80x94Oxe2x80x94(C1-C6 alkyl),
(27) xe2x80x94Oxe2x80x94(C2-C5 alkyl)-COOH, or
(28) xe2x80x94Sxe2x80x94(C1-C6 alkyl),
(C) xe2x80x94RN-arylRN-aryl where xe2x80x94RN-aryl is as defined above,
(D) xe2x80x94RN-arylxe2x80x94RN-heteroaryl where xe2x80x94RN-aryl and xe2x80x94RN-heteroaryl are as defined above,
(E) xe2x80x94RN-heteroarylxe2x80x94RN-aryl where xe2x80x94RN-aryl and xe2x80x94RN-heteroaryl are as defined above,
(F) xe2x80x94RN-heteroarylxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(G) xe2x80x94RN-arylxe2x80x94Oxe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(H) xe2x80x94RN-arylxe2x80x94Sxe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(I) xe2x80x94RN-heteroarylxe2x80x94Oxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(J) xe2x80x94RN-heteroarylxe2x80x94Sxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(K) xe2x80x94RN-arylxe2x80x94COxe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(L) xe2x80x94RN-arylxe2x80x94COxe2x80x94RN-heteroaryl where xe2x80x94RN-aryl and RN-heteroaryl are as defined above,
(M) xe2x80x94RN-arylxe2x80x94SO2xe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(N) xe2x80x94RN-heteroarylxe2x80x94COxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(O) xe2x80x94RN-heteroarylxe2x80x94SO2xe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(P) xe2x80x94RN-arylxe2x80x94Oxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-aryl is as defined above,
(Q) xe2x80x94RN-arylxe2x80x94Sxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-aryl is as defined above,
(R) xe2x80x94RN-heteroarylxe2x80x94Oxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-heteroaryl is as defined above, or
(S) xe2x80x94RN-heteroarylxe2x80x94Sxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-heteroaryl is as defined above,
(II) Axe2x80x94XNxe2x80x94 where XN is xe2x80x94COxe2x80x94,
wherein A is
(A) xe2x80x94Txe2x80x94E(Q)mxe2x80x2,
(1) where xe2x80x94T is: 
where
(a) x=1 when y=1 and x=2 when y=0,
(b) m is 0, 1, 2 or 3,
(c) the values of x and y vary independently on each carbon when m is 2 and 3, and
(d) Rxe2x80x2xe2x80x3 varies independently on each carbon and is H, (C1-C2) alkyl, phenyl, or phenyl(C1-C3)alkyl;
(2) xe2x80x94E is
(a) C1-C5 alkyl, but only if mxe2x80x2 does not equal 0,
(b) methylthioxy(C2-C4)alkyl,
(c) an aryl group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,
(d) a heterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,
(e) a mono or fused ring cycloalkyl group having 5 to 10 carbon atoms,
(f) biphenyl,
(g) diphenyl ether,
(h) diphenylketone,
(i) phenyl(C1-C8)alkyloxyphenyl, or
(j) C1-C6 alkoxy;
(3) xe2x80x94Q is
(a) C1-C3 alkyl,
(b) C1-C3 alkoxy,
(c) C1-C3 alkylthioxy,
(d) C1-C6 alkylacylamino,
(e) C1-C6 alkylacyloxy,
(f) amido (including primary, C1-C6 alkyl and phenyl secondary and tertiary amino moieties),
(g) C1-C6 alkylamino
(h) phenylamino,
(i) carbamyl (including C1-C6 alkyl and phenyl amides and esters),
(j) carboxyl (including C1-C6 alkyl and phenyl esters),
(k) carboxy(C2-C5)alkoxy,
(l) carboxy(C2-C5)alkylthioxy,
(m) heterocyclylacyl,
(n) heteroarylacyl, or
(o) hydroxyl;
(4)mxe2x80x2 is 0, 1, 2 or 3;
(B) xe2x80x94E(Q)mxe2x80x3, wherein E and xe2x80x94Q are as defined as above and mxe2x80x3 is 0, 1, 2, or 3;
(C) xe2x80x94Txe2x80x94E wherein xe2x80x94E and xe2x80x94Q are as defined as above; or
(D) xe2x80x94E wherein xe2x80x94E is as defined as above;
(III) xe2x80x94COxe2x80x94(C1-C6 alkyl) where alkyl is unsubstituted or substituted with one or two:
(A)xe2x80x94OH,
(B) xe2x80x94C1-C6 alkoxy,
(C) xe2x80x94C1-C6 thioalkoxy,
(D) xe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is xe2x80x94H, C1-C6 alkyl or -xcfx86,
(E) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) xe2x80x94COxe2x80x94RN-4 where RN-4 is as defined above,
(G) xe2x80x94SO2xe2x80x94(C1-C8 alkyl),
(H) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) xe2x80x94NHxe2x80x94COxe2x80x94(C1-C6 alkyl),
(J) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is as defined above,
(K) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) xe2x80x94RN-4 where RN-4 is as defined above,
(M) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(N) xe2x80x94Oxe2x80x94COxe2x80x94NRN-8RN-8 where the RN-8 is the same or different and are as defined above, or
(O) xe2x80x94Oxe2x80x94(C1-C5 alkyl)-COOH,
(IV) xe2x80x94COxe2x80x94(C1-C3 alkyl)xe2x80x94Oxe2x80x94(C1-C3 alkyl) where alkyl is unsubstituted or substituted with one or two
(A) xe2x80x94OH,
(B) xe2x80x94C1-C6 alkoxy,
(C) xe2x80x94C1-C6 thioalkoxy,
(D) xe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is xe2x80x94H, C1-C6 alkyl or -xcfx86,
(E) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) xe2x80x94COxe2x80x94RN-4 where RN-4 is as defined above,
(G) xe2x80x94SO2xe2x80x94(C1-C8 alkyl),
(H) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) xe2x80x94NHxe2x80x94COxe2x80x94(C1-C6 alkyl),
(J) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is as defined above,
(K) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) xe2x80x94RN-4 where RN-4 is as defined above,
(M) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(N) xe2x80x94Oxe2x80x94COxe2x80x94NRN-8RN-8 where the RN-8 are the same or different and are as defined above, or
(O) xe2x80x94Oxe2x80x94(C1-C5 alkyl)-COOH,
(V) xe2x80x94COxe2x80x94(C1-C3 alkyl)xe2x80x94Sxe2x80x94(C1-C3 alkyl) where alkyl is unsubstituted or substituted with one or two
(A) xe2x80x94OH,
(B) xe2x80x94C1-C6 alkoxy,
(C) xe2x80x94C1-C6 thioalkoxy,
(D) xe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is xe2x80x94H, C1-C6 alkyl or -xcfx86,
(E) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) xe2x80x94COxe2x80x94RN-4 where RN-4 is as defined above,
(G) xe2x80x94SO2xe2x80x94(C1-C8 alkyl),
(H) xe2x80x94SO2xe2x80x94NRN-2 RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) xe2x80x94NHxe2x80x94COxe2x80x94(C1-C6 alkyl),
(J) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is as defined above,
(K) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) xe2x80x94RN-4 where RN-4 is as defined above,
(M) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(N) xe2x80x94Oxe2x80x94COxe2x80x94NRN8RN-8 where the RN-8 are the same or different and are as defined above, or
(O) xe2x80x94Oxe2x80x94(C1-C5 alkyl)-COOH,
(VI) xe2x80x94COxe2x80x94CH(xe2x80x94(CH2)0-2xe2x80x94Oxe2x80x94RN-10)xe2x80x94(CH2)0-2xe2x80x94RN-aryl/RN-heteroaryl) where RN-aryl and RN-heteroaryl are as defined above, where RN-1 0 is:
(A) xe2x80x94H,
(B) C1-C6 alkyl,
(C) C3-C7 cycloalkyl,
(D) C2-C6 alkenyl with one double bond,
(E) C2-C6 alkynyl with one triple bond,
(F) R1-aryl where R1-aryl is as defined above, or
(G) RN-heteroaryl where RN-heteroaryl is as defined above;
xe2x80x83where B is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94N(C1-C6 alkyl)-;
where RC is:
(I) xe2x80x94(C1-C10)alkyl-K1-3 in which:
(A) the alkyl chain is unsubstituted or substituted with one xe2x80x94OH,
(B) the alkyl chain is unsubstituted or substituted with one C1-C6 alkoxy unsubstituted or substituted with 1-5 xe2x80x94F,
(C) the alkyl chain is unsubstituted or substituted with one xe2x80x94O-xcfx86,
(D) the alkyl chain is unsubstituted or substituted with 1-5 xe2x80x94F,
(E) the alkyl chain is unsubstituted or substituted with a combination of up to three atoms of oxygen and sulfur each such atom replacing one carbon,
(F) each K is:
(1) H,
(2) C1-C3 alkyl,
(3) C1-C3 alkoxy,
(4) C1-C3 alkylthioxy,
(5) C1-C6 alkylacylamino,
(6) C1-C6 alkylacyloxy,
(7) amido
(8) C1-C6 alkylamino
(9) phenylamino,
(10) carbamyl
(11) carboxyl
(12) carboxy(C2-C5)alkoxy,
(13) carboxy(C2-C5)alkylthioxy,
(14) heterocyclylacyl,
(15) heteroarylacyl,
(16) amino unsubstituted or substituted with C1-C6 alkyl,
(17) hydroxyl, or
(18) carboxyl methyl ester;
(II)xe2x80x94(CH2)0-3xe2x80x94J-[(xe2x80x94(CH2)0-3-K]1-3 where K is as defined above and J is:
(A) a 5 to 7 atom monocyclic aryl group,
(B) a 8 to 12 atom multicyclic aryl group,
(C) a 5 to 7 atom heterocyclic group,
(D) a 8 to 12 atom multicyclic heterocyclic group, or
(E) a 5 to 10 atom monocyclic or multicyclic cycloalkyl group;
(III) xe2x80x94(CH2)0-3xe2x80x94(C3-C7) cycloalkyl where cycloalkyl can be unsubstituted or substituted with one, two or three
(A) C1-C3 alkyl unsubstituted or substituted with 1, 2, 3, or 4 xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(B) xe2x80x94COxe2x80x94OH,
(C) xe2x80x94COxe2x80x94Oxe2x80x94(C1-C4 alkyl),
(D) xe2x80x94OH, or
(E) C1-C6 alkoxy,
(IV) xe2x80x94(CH2)2-6xe2x80x94OH,
(V) (CRC-xRC-y)0-4xe2x80x94RC-aryl where RC-x and RC-y are xe2x80x94H, C1-C4 alkyl and xcfx86- and RC-aryl is the same as RN-aryl,
(VI) xe2x80x94(CH2)0-4xe2x80x94RC-heteroaryl where RC-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) isoxazolyl,
(Q) pyrazolyl,
(R) indolizinyl,
(S) indazolyl,
(T) benzothiazolyl,
(U) benzimidazolyl,
(V) benzofuranyl,
(W) furanyl,
(X) thienyl,
(Y) pyrrolyl,
(Z) oxadiazolyl,
(AA) thiadiazolyl,
(BB) triazolyl,
(CC) tetrazolyl,
(DD) 1,4-benzodioxan
(EE) purinyl,
(FF) oxazolopyridinyl,
(GG) imidazopyridinyl,
(HH) isothiazolyl,
(II) naphthyridinyl,
(JJ) cinnolinyl,
(KK) carbazolyl,
(LL) xcex2-carbolinyl,
(MM) isochromanyl,
(NN) chromanyl,
(OO) furazanyl,
(PP) tetrahydroisoquinoline,
(QQ) isoindolinyl,
(RR) isobenzotetrahydrofuranyl,
(SS) isobenzotetrahydrothienyl,
(TT) isobenzothiophenyl,
(UU) benzoxazolyl, or
(VV) pyridopyridinyl,
(VII ) xe2x80x94(CH2)0-4xe2x80x94RC-heterocycle where RC-heterocycle is the same as R1-heterocycle,
(VIII) xe2x80x94C(RC-1)(RC-2)xe2x80x94COxe2x80x94NHxe2x80x94RC-3 where RC-1 and RC-2 are the same or different and are:
(A) xe2x80x94H,
(B) xe2x80x94C1-C6 alkyl,
(C) xe2x80x94(C1-C4 alkyl)-RCxe2x80x2-aryl where RCxe2x80x2-aryl is as defined above for R1-aryl,
(D) xe2x80x94(C1-C4 alkyl)-RC-heteroaryl where RC-heteroaryl is as defined above,
(E) xe2x80x94(C1-C4 alkyl)-RC-heterocycle where RC-heterocycle is as defined above,
(F) xe2x80x94RC-heteroaryl where RC-heteroaryl is as defined above,
(G) xe2x80x94RC-heterocycle where RC-heterocycle is as defined above,
(H) xe2x80x94(CH2)14xe2x80x94OH,
(I) xe2x80x94(CH2)1-4xe2x80x94RC-4xe2x80x94(CH2)1-4xe2x80x94RCxe2x80x2-aryl where RC-4 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94NHRC-5xe2x80x94 where RC-5 is C1-C6 alkyl, and where RCxe2x80x2-aryl is as defined above,
(J) xe2x80x94(CH2)1-4xe2x80x94RC-4xe2x80x94(CH2)1-4xe2x80x94RC-heteroaryl where RC-4 and RC-heteroaryl are as defined above, or
(K) xe2x80x94RCxe2x80x2-aryl where RCxe2x80x2-aryl is as defined above,
and where RC-3 is:
(A) xe2x80x94H,
(B) xe2x80x94C1-C6 alkyl,
(C) xe2x80x94RCxe2x80x2-aryl where RCxe2x80x2-aryl is as defined above,
(D) xe2x80x94RC-heteroaryl where RC-heteroaryl is as defined above,
(E) xe2x80x94RC-heterocycle where RC-heterocycle is as defined above,
(F) xe2x80x94(C1-C4 alkyl)-RCxe2x80x2-aryl where RCxe2x80x2-aryl is as defined above,
(G) xe2x80x94(C1-C4 alkyl)-RC-heteroaryl where RC-heteroaryl is as defined above, or
(H) xe2x80x94(C1-C4 alkyl)-RC-heterocycle where RC-heterocycle is as defined above,
(IX) xe2x80x94CH(xcfx86)2,
(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring where heteroaryl is as defined above and phenyl and heteroaryl are unsubstituted or substituted with one, two or three:
(A) C1-C3 alkyl,
(B) xe2x80x94CF3,
(C) xe2x80x94F, Cl, xe2x80x94Br and xe2x80x94I,
(D) C1-C3 alkoxy,
(E) xe2x80x94OCF3,
(F) xe2x80x94NH2,
(G) xe2x80x94OH, or
(H) xe2x80x94Cxe2x89xa1N,
(XI) xe2x80x94CH2xe2x80x94Cxe2x89xa1CH;
(XII) xe2x80x94(CH2)0-2xe2x80x94CHRC-5xe2x80x94(CH2)0-1-xcfx86 where RC-5 is:
(A) H, or
(B)xe2x80x94CH2xe2x80x94OH;
(XIII) xe2x80x94CH(-xcfx86)-COxe2x80x94O(C1-C3 alkyl);
(XIV) xe2x80x94CH(xe2x80x94CH2xe2x80x94OH)xe2x80x94CH(xe2x80x94OH)-xcfx86- NO2;
(XV) xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94OH;
(XVI) xe2x80x94CH2xe2x80x94NHxe2x80x94CH2xe2x80x94CH(xe2x80x94Oxe2x80x94CH2xe2x80x94CH3)2;
(XVII) xe2x80x94(C2-C8) alkynyl; or
(XVIII) xe2x80x94H; or a pharmaceutically acceptable salt thereof.
Disclosed is the use of a hydroxyethylene compound of formula (XII): 
where R1, R2, RC, and RN are as defined immediately above, and pharmaceutically acceptable salts thereof for the manufacture of a medicament for use in treating a patient who has, or in preventing a patient from getting, a disease or condition selected from Alzheimer""s disease, mild cognitive impairment, Down""s syndrome, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy body type of Alzheimer""s disease or central or preipheral amyloid diseases and who is in need of such treatment.
The present invention provides hydroxyethylene compounds of formula (XII) which are useful in treating and preventing Alzheimer""s disease. The anti-Alzheimer""s hydroxyethylene compounds of formula (XII) are made by methods well known to those skilled in the art from starting compounds known to those skilled in the art. The process chemistry is well known to those skilled in the art. The most general process to prepare the hydroxyethylene compounds of formula (XII) is set forth in CHART A, as defined within. The chemistry is straight forward and in summary involves the steps of N-protecting an amino acid (I) starting material to produce the corresponding protected amino acid (II), amino-dehydroxylation of the protected amino acid (II) with the appropriate amine in the presence of a coupling agent to produce the corresponding protected amide (III), reduction of the protected amide to the corresponding aldehyde (IV), formation of the terminal olefin as described (V), peracid epoxidation of the olefin (V) to produce the corresponding epoxide (VI), opening of the epoxide (VI) with an amide (VII) to produce the corresponding protected alcohol (VIII), cyclization of the protected alcohol (VIII) to produce the protected lactone (IX) which then has the nitrogen protecting group removed to produce the corresponding amine (X), which is then reacted with an amide forming agent of the formula (RN-1xe2x80x94XN)2O or RN-1xe2x80x94XNxe2x80x94X2 or RNxe2x88x921xe2x80x94XNxe2x80x94OH, for example, to produce the lactone (XI), opening of the lactone (XI) with a C-terminal amine, RCxe2x80x94NH2 to produce the anti-Alzheimer hydroxyethylene compounds of formula (XII). One skilled in the art will appreciate that these are all well known reactions in organic chemistry. A chemist skilled in the art, knowing the chemical structure of the biologically active hydroxyethylene compounds of formula (XII) would be able to prepare them by known methods from known starting materials without any additional information. The explanation below therefore is not necessary but is deemed helpful to those skilled in the art who desire to make the compounds of the present invention.
The backbone of the compounds of the present invention is a hydroxyethylene moiety. It can be readily prepared by methods disclosed in the literature and known to those skilled in the art. For example, Henning, R. xe2x80x9cSynthetic Routes to Different Classes of Natural Products and Analogs Thereof. Synthesis of Hydroxyethylene Isosteric Dipeptides.xe2x80x9d In Organic Synthesis Highlights II; VCH: Weinheim, Germany, 1995; pp 251-259 discloses processes to prepare hydroxyethylene type compounds.
CHART A, as defined within, sets forth a general method used in the present invention to prepare the appropriately substituted hydroxyethylene compounds of formula (XII). The anti-Alzheimer hydroxyethylene compounds of formula (XII) are prepared by starting with the corresponding amino acid (I). The amino acids (I) are well known to those skilled in the art or can be readily prepared from known compounds by methods well known to those skilled in the art. The hydroxyethylene compounds of formula (XII) have at least three enantiomeric centers which give 8 enantiomers, the S, S, R stereochemistry being preferred. The first of these enantiomeric centers derives from the amino acid starting material (I). It is preferred to commercially obtain or produce the desired enantiomer (S) rather than produce an enantiomerically impure mixture and then have to separate out the desired enantiomer (S). It is preferred to start the process with enantiomerically pure (S)-amino acid (I) of the same configuration as that of the hydroxyethylene product. For the amino acids (I), R1 is:
(I) C1-C6 alkyl, unsubstituted or substituted with one, two or three C1-C3 alkyl, xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, xe2x80x94OH, xe2x80x94NH2, xe2x80x94Cxe2x89xa1N, xe2x80x94CF3, or xe2x80x94N3,
(II) xe2x80x94(CH2)1-2xe2x80x94Sxe2x80x94CH3,
(III) xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94CH3,
(IV) xe2x80x94CH2xe2x80x94(C2-C6 alkenyl) unsubstituted or substituted by one xe2x80x94F,
(V) xe2x80x94(CH2)0-3(R1-aryl) where R1-aryl is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinyl unsubstituted or substituted on the aryl ring with one or two of the following substituents which can be the same or different:
(A) C1-C3 alkyl,
(B) xe2x80x94CF3,
(C) xe2x80x94F, Cl, xe2x80x94Br and xe2x80x94I,
(D) C1-C3 alkoxy,
(E) xe2x80x94Oxe2x80x94CF3,
(F) xe2x80x94NH2,
(G) xe2x80x94OH, or
(H) xe2x80x94Cxe2x89xa1N,
(VI) xe2x80x94(CH2)n1xe2x80x94(R1-heteroaryl) where n1 is 0, 1, 2, or 3 and R1-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) imidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) xcex2-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrothienyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
xe2x80x83where the R1-heteroaryl group is bonded to xe2x80x94(CH2)0-3xe2x80x94 by any ring atom of the parent RN-heteroaryl group substituted by hydrogen such that the new bond to the R1-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is unsubstituted or substituted with one or two:
(1) C1-C3 alkyl,
(2) xe2x80x94CF3,
(3) xe2x80x94F, Cl, xe2x80x94Br, or xe2x80x94I,
(4) C1-C3 alkoxy,
(5) xe2x80x94Oxe2x80x94CF3,
(6) xe2x80x94NH2,
(7) xe2x80x94OH, or
(8) xe2x80x94Cxe2x89xa1N,
xe2x80x83with the proviso that when n1 is zero R1-heteroaryl is not bonded to the carbon chain by nitrogen, or
(VII) xe2x80x94(CH2)n1xe2x80x94(R1-heterocycle) where n1 is as defined above and R1 heterocycle is:
(A) morpholinyl,
(B) thiomorpholinyl,
(C) thiomorpholinyl S-oxide,
(D) thiomorpholinyl S,S-dioxide,
(E) piperazinyl,
(F) homopiperazinyl,
(G) pyrrolidinyl,
(H) pyrrolinyl,
(I) tetrahydropyranyl,
(J) piperidinyl,
(K) tetrahydrofuranyl, or
(L) tetrahydrothiophenyl,
xe2x80x83where the R1-heterocycle group is bonded by any atom of the parent R1-heterocycle group substituted by hydrogen such that the new bond to the R1-heteroaryl group replaces the hydrogen atom and its bond, where heterocycle is unsubstituted or substituted with one or two:
(1) xe2x95x90O,
(2) C1-C3 alkyl,
(3) xe2x80x94CF3,
(4) xe2x80x94F, Cl, xe2x80x94Br and xe2x80x94I,
(5) C1-C3 alkoxy,
(6) xe2x80x94Oxe2x80x94CF3,
(7) xe2x80x94NH2,
(8)xe2x80x94OH, or
(9) xe2x80x94Cxe2x89xa1N,
with the proviso that when n1 is zero R1-heterocycle is not bonded to the carbon chain by nitrogen. Typically, R1 is (V) xe2x80x94(CH2)0-1(R1-aryl) or (VI) xe2x80x94(CH2)n1xe2x80x94(R1-heteroaryl). It is preferred that R1 is (V) xe2x80x94(CH2)xe2x80x94(R1-aryl) or (VI) xe2x80x94(CH2)-(R1-heteroaryl). It is more preferre that R1 is xe2x80x94(CH2)xe2x80x94(R1-aryl) where R1-aryl is phenyl. It is even more preferred that R1 is xe2x80x94(CH2)xe2x80x94(R1-aryl) where R1-aryl is phenyl substituted with two xe2x80x94F. It is most preferred that the xe2x80x94F substitution is 3,5 on the phenyl ring.
When R1 is R1-heteroaryl or R1-heterocycle the bond from the R1-heteroaryl or R1-heterocycle group to the xe2x80x94(CH2)n1xe2x80x94 group can be from any ring atom which has an available valence provided that such bond does not result in formation of a charged species or unstable valence. This means that the R1-heteroaryl or R1-heterocycle group is bonded to xe2x80x94(CH2)n1-by any ring atom of the parent R1-heteroaryl or R1-heterocycle group which was substituted by hydrogen such that the new bond to the R1-heteroaryl or R1-heterocycle group replaces the hydrogen atom and its bond.
The first step of the process is to protect the free amino group of the (S)-amino acid (I) with an amino protecting group to produce the (S)-protected amino acid (II) by methods well known to those skilled in the art. Amino protecting groups are well known to those skilled in the art. See for example, xe2x80x9cProtecting Groups in Organic Synthesisxe2x80x9d, John Wiley and sons, New York, N.Y., 2nd ed., 1991, Chapter 7; xe2x80x9cProtecting Groups in Organic Chemistryxe2x80x9d, Plenum Press, New York, N.Y., 1973, Chapter 2. The function of the amino protecting group is to protect the free amino functionality (xe2x80x94NH2) during subsequent reactions on the (S)-amino acid (I) which would not proceed well either because the amino group would react and be functionalized in a way that is inconsistent with its need to be free for subsequent reactions or the free amino group would interfere in the reaction. When the amino protecting group is no longer needed, it is removed by methods well known to those skilled in the art. By definition the amino protecting group must be readily removable as is known to those skilled in the art by methods well known to those skilled in the art. Suitable amino PROTECTING GROUPs include t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl, isobomyloxycarbonyl, -phenyl-C(xe2x95x90N)xe2x80x94H, and 1-piperidyloxycarbonyl. It is preferred that the protecting group be t-butoxycarbonyl (BOC) and benzyloxycarbonyl (CBZ), it is more preferred that the protecting group be t-butoxycarbonyl. One skilled in the art will understand the preferred methods of introducing a t-butoxycarbonyl or benzyloxycarbonyl protecting group and may additionally consult T. W. Green and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, John Wiley and Sons, 2nd ed., 1991, at 327-335 for guidance.
The (S)-protected amino acid (II) is transformed to the corresponding (S)-protected amide compound (III) by means well known to those skilled in the art for the production of an amide from a carboxylic acid and an amine or hydroxylamine. The means and reaction conditions for producing the (S)-protected amide compound (III) include, for example, the use of a coupling agent such as, for example, dicyclohexylcarbodiimide, 1,1-carbonyldiumidazole, POCl3, TiCl4, SO2ClF, benzotriazol-1-yl diethyl phosphate, or N, N, Nxe2x80x2, Nxe2x80x2-tetramethyl(succinimido)uronium tetrafluoroborate in the presence of an amine or hydroxylamine. 1,1-Carbonyldiimidazole is a preferred coupling agent and N-methyl-O-methylhydroxylamine is a preferred hydroxylamine. The reaction is carried out for a period of time between 1 hour and 3 days at temperatures ranging from xe2x88x9278xc2x0 to elevated temperature up to the reflux point of the solvent employed. It is preferred to conduct the reaction between 0xc2x0 and 50xc2x0.
The (S)-protected amide compound (III) is then reduced by means well known to those skilled in the art for reduction of a amide to the corresponding aldehyde, affording the corresponding aldehyde (IV). The means and reaction conditions for reducing the (S)-protected amide compound (III) to the corresponding aldehyde (IV) include, for example, sodium borohydride, lithium borohydride, borane, diisobutylaluminum hydride, and lithium aluminium hydride. Lithium aluminium hydride is the preferred reducing agent. The reductions are carried out for a period of time between 1 hour and 3 days at temperatures ranging from xe2x88x9278xc2x0 to room temperature. It is preferred to conduct the reduction between xe2x88x9220xc2x0 and room temperature. The preferred combination of reducing agents and reaction conditions needed are known to those skilled in the art, see for example, Larock, R. C. in Comprehensive Organic Transformations, VCH Publishers, 1989.
The aldehyde (IV) is transformed to the corresponding olefin (V) by means known to those skilled in the art. An example of such a reaction is the reaction of the aldehyde (IV) with a phosphorous ylide to produce the desired olefin. Such phosphorous ylides include methyltriphenylphosphonium bromide. Reaction conditions include temperatures ranging from xe2x88x92100xc2x0 up to the reflux temperature of the solvent employed; preferred temperature ranges are between xe2x88x92100xc2x0 and 0xc2x0.
Peracid epoxidation of the olefin (V) affords the epoxide (VI). Other methods for the conversion of an olefin to an epoxide are known to those skilled in the art. The means for producing the epoxide (VI) include, for example, the use of a peracid such as, for example, peracetic acid, perbenzoic, trifluoroperacetic acid, 3,5-dinitroperoxybenzoic acid, and m-chloroperbenzoic acid.
The epoxide (VI) is then reacted with the appropriate amide (VII) by means known to those skilled in the art which opens the epoxide to produce the desired corresponding protected alcohol (VIII). Reaction of the epoxide (VI) with the amide (VII) produces a mixture of enantiomers. This enantiomeric mixture is then separated by means known to those skilled in the art such as selective low-temperature recrystallization or chromatographic separation, most preferably by HPLC, employing commercially available chiral columns. The enantiomer that is used in the remainder of the process of CHART A is the (S,S, R)-alcohol (VIII).
The protected-alcohol (VIII) is transformed to the corresponding protected lactone (IX) by means known to those skilled in the art. A preferred means is by reaction with an acid catalyst, for example, but not limited to, p-toluenesulfonic acid and the like. Reactions are conducted at temperatures ranging from xe2x88x9278xc2x0 up to the reflux temperature of the solvent employed; preferred temperature ranges are between 0xc2x0 and 50xc2x0.
The amine moiety or the protected lactone (IX) is deprotected to the corresponding amine (X) by means known to those skilled in the art for removal of amine protecting group. Suitable means for removal of the amine protecting group depends on the nature of the protecting group. Those skilled in the art, knowing the nature of a specific protecting group, know which reagent is preferable for its removal. For example, it is preferred to remove the preferred protecting group, BOC, by dissolving the protected lactone (IX) in a trifluoroacetic acid/dichloromethane mixture. When complete, the solvents are removed under reduced pressure to give the corresponding lactone (as the corresponding salt, i.e. trifluoroacetic acid salt) which is used without further purification. However, if desired, the lactone can be purified further by means well known to those skilled in the art, such as for example, recrystallization. Further, if the non-salt form is desired that also can be obtained by means known to those skilled in the art, such as for example, preparing the free base amine via treatment of the salt with mild basic conditions. Additional BOC deprotection conditions and deprotection conditions for other protecting groups can be found in T. W. Green and P. G. M. Wuts in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, John Wiley and Sons, 1991, p. 309 and following. Chemically suitable salts include trifluoroacetate, and the anion of mineral acids such as chloride, sulfate, phosphate; preferred is trifluoroacetate.
The amine (X) is then reacted with an appropriately substituted-amide-forming-agent such as anhydride, acyl halide, or acid of the formula (RN-1xe2x80x94XN)2O or RN-1xe2x80x94XNxe2x80x94X2 or RN-1xe2x80x94XNxe2x80x94OH by nitrogen-acylation means known to those skilled in the art to produce the corresponding lactone (XI). Nitrogen acylation conditions for reaction of the amine (X) with an amide forming agent to produce the corresponding lactone (XI) are known to those skilled in the art and can be found in R. C. Larock in Comprehensive Organic Transformations, VCH Publishers, 1989, p. 981, 979, and 972. RN includes:
(I) RN-1 XNxe2x80x94 where XN is:
(A) xe2x80x94COxe2x80x94,
(B) xe2x80x94SO2xe2x80x94,
(C) xe2x80x94(CRxe2x80x2Rxe2x80x3) 1-6 where Rxe2x80x2 and Rxe2x80x3 are the same or different and are xe2x80x94H or C1-C4 alkyl,
(D) xe2x80x94COxe2x80x94(CRxe2x80x2Rxe2x80x3)1-6xe2x80x94XN-1 where XN-1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94NRxe2x80x2Rxe2x80x3xe2x80x94 and where Rxe2x80x2 and Rxe2x80x3 are as defined above,
(E) a single bond;
where RN-1 is:
(A) RN-aryl where RN-aryl is phenyl, 1-naphthyl and 2-naphthyl unsubstituted or substituted with one, two, three or four of the following substituents which can be the same or different and are:
(1) C1-C6 alkyl,
(2) xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(3) xe2x80x94OH,
(4) xe2x80x94NO2,
(5)xe2x80x94COxe2x80x94OH,
(6) xe2x80x94Cxe2x89xa1N,
(7) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are:
(a) xe2x80x94H,
(b) xe2x80x94C1-C6 alkyl unsubstituted or substituted with one
(i) xe2x80x94OH, or
(ii) xe2x80x94NH2,
(c) xe2x80x94C1-C6 alkyl unsubstituted or substituted with one to three xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(d) xe2x80x94C3-C7 cycloalkyl,
(e) xe2x80x94(C1-C2 alkyl)xe2x80x94(C3-C7 cycloalkyl),
(f) xe2x80x94(C1-C6 alkyl)xe2x80x94Oxe2x80x94(C1-C3 alkyl),
(g) xe2x80x94C1-C6 alkenyl with one or two double bonds,
(h) xe2x80x94C1-C6 alkynyl with one or two triple bonds,
(i) xe2x80x94C1-C6 alkyl chain with one double bond and one triple bond,
(j) xe2x80x94R1-aryl where R1-aryl is as defined above, or
(k) xe2x80x94R1-heteroaryl where R1-heteroaryl is as defined above,
(8) xe2x80x94COxe2x80x94(C3-C12 alkyl),
(9) xe2x80x94COxe2x80x94(C3-C6 cycloalkyl),
(10) xe2x80x94COxe2x80x94R1-heteroaryl where R1-heteroaryl is as defined above,
(11) xe2x80x94COxe2x80x94R1-heterocycle where R1-heterocycle is as defined above,
(12) xe2x80x94COxe2x80x94RN-4 where RN-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with one or two C1-C3 alkyl,
(13) xe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is:
(a) C1-C6 alkyl, or
(b) xe2x80x94(CH2)0-2xe2x80x94(R1-aryl) where R1-aryl is as defined above,
(14) xe2x80x94SO2-NRN-2RN-3 where RN-2 and RN-3 are as defined above,
(15) xe2x80x94SOxe2x80x94(C1-C8 alkyl),
(16) xe2x80x94SO2xe2x80x94(C3-C12 alkyl),
(17) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is as defined above,
(18) xe2x80x94NHxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(19) xe2x80x94Nxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(20) xe2x80x94N(C1-C3 alkyl)-COxe2x80x94RN-5 where RN-5 is as defined above,
(21) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 can be the same or different and are as defined above,
(22) xe2x80x94RN-4 where RN-4 is as defined above,
(23) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(24) xe2x80x94Oxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(25) xe2x80x94Oxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(26) xe2x80x94Oxe2x80x94(C1-C6 alkyl),
(27) xe2x80x94Oxe2x80x94(C2-C5 alkyl)-COOH,
(28) xe2x80x94Sxe2x80x94(C1-C6 alkyl),
(29) C1-C6 alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5xe2x80x94F,
(30) xe2x80x94Oxe2x80x94(C1-C6 alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 xe2x80x94F, or
(31) xe2x80x94O-xcfx86,
(B) xe2x80x94RN-heteroaryl where RN-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) imidazolyl,
(Q) isoxazolyl,
(R) pyrazolyl,
(S) oxazolyl,
(T) thiazolyl,
(U) indolizinyl,
(V) indazolyl,
(W) benzothiazolyl,
(X) benzimidazolyl,
(Y) benzofuranyl,
(Z) furanyl,
(AA) thienyl,
(BB) pyrrolyl,
(CC) oxadiazolyl,
(DD) thiadiazolyl,
(EE) triazolyl,
(FF) tetrazolyl,
(GG) 1,4-benzodioxan
(HH) purinyl,
(II) oxazolopyridinyl,
(JJ) imidazopyridinyl,
(KK) isothiazolyl,
(LL) naphthyridinyl,
(MM) cinnolinyl,
(NN) carbazolyl,
(OO) xcex2-carbolinyl,
(PP) isochromanyl,
(QQ) chromanyl,
(RR) furazanyl,
(SS) tetrahydroisoquinoline,
(TT) isoindolinyl,
(UU) isobenzotetrahydrofuranyl,
(VV) isobenzotetrahydrothienyl,
(WW) isobenzothiophenyl,
(XX) benzoxazolyl, or
(YY) pyridopyridinyl,
xe2x80x83where the RN-heteroaryl group is bonded by any atom of the parent RN-heteroaryl group substituted by hydrogen such that the new bond to the RN-heteroaryl group replaces the hydrogen atom and its bond, where heteroaryl is unsubstituted or substituted with one or two:
(1) C1-C6 alkyl,
(2) xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(3) xe2x80x94OH,
(4) xe2x80x94NO2,
(5) xe2x80x94COxe2x80x94OH,
(6) xe2x89xa1CN,
(7) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are:
(a) xe2x80x94H,
(b) xe2x80x94C1-C6 alkyl unsubstituted or substituted with one
(i) xe2x80x94OH, or
(ii) xe2x80x94NH2,
(c) xe2x80x94C1-C6 alkyl unsubstituted or substituted with 1, 2, or 3 xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(d) xe2x80x94C3-C7 cycloalkyl,
(e) xe2x80x94(C1-C2 alkyl)xe2x80x94(C3-C7 cycloalkyl),
(f) xe2x80x94(C1-C6 alkyl)xe2x80x94Oxe2x80x94(C1-C3 alkyl),
(g) xe2x80x94C1-C6 alkenyl with one or two double bonds,
(h) xe2x80x94C1-C6 alkynyl with one or two triple bonds,
(i) xe2x80x94C1-C6 alkyl chain with one double bond and one triple bond,
(j) xe2x80x94R1-aryl where R1-aryl is as defined above, or
(k) R1-heteroaryl where R1-heteroaryl is as defined above,
(8) xe2x80x94COxe2x80x94(C3-C12 alkyl),
(9) xe2x80x94COxe2x80x94(C3-C6 cycloalkyl),
(10) xe2x80x94COxe2x80x94R1-heteroaryl where R1-heteroaryl is as defined above,
(11) xe2x80x94COxe2x80x94R1-heterocycle where R1-heterocycle is as defined above,
(12) xe2x80x94COxe2x80x94RN-4 where RN-4 is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where each group is unsubstituted or substituted with one or two C1-C3 alkyl,
(13) xe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is:
(a) C1-C6 alkyl, or
(b) xe2x80x94(CH2)0-2xe2x80x94(R1-aryl) where R1-aryl is as defined above,
(14) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are as defined above,
(15) xe2x80x94SOxe2x80x94(C1-C8 alkyl),
(16) xe2x80x94SO2xe2x80x94(C3-C12 alkyl),
(17) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-5 where RN-5 is as defined above,
(18) xe2x80x94NHxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(19) xe2x80x94Nxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(20) xe2x80x94N(C1-C3 alkyl)-COxe2x80x94RN5 where RN-5 is as defined above,
(21) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 can be the same or different and are as defined above,
(22) xe2x80x94RN-4 where RN-4 is as defined above,
(23) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(24) xe2x80x94Oxe2x80x94COxe2x80x94N(C1-C3 alkyl)2,
(25) xe2x80x94Oxe2x80x94CSxe2x80x94N(C1-C3 alkyl)2,
(26) xe2x80x94Oxe2x80x94(C1-C6 alkyl),
(27) xe2x80x94Oxe2x80x94(C2-C5 alkyl)-COOH, or
(28) xe2x80x94Sxe2x80x94(C1-C6 alkyl),
(C) xe2x80x94RN-arylxe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(D) xe2x80x94RN-arylxe2x80x94RN-heteroaryl where xe2x80x94RN-aryl and xe2x80x94RN-heteroaryl are as defined above,
(E) xe2x80x94RN-heteroarylRN-aryl where xe2x80x94RN-aryl and xe2x80x94RN-heteroaryl are as defined above,
(F) xe2x80x94RN-heteroarylxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(G) xe2x80x94RN-arylxe2x80x94Oxe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(H) xe2x80x94RN-arylxe2x80x94Sxe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(I) xe2x80x94RN-heteroarylxe2x80x94Oxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(J) xe2x80x94RN-heteroarylxe2x80x94Sxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(K) xe2x80x94RN-arylxe2x80x94COxe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(L) xe2x80x94RN-arylxe2x80x94COxe2x80x94RN-heteroaryl where xe2x80x94RN-aryl and RN-heteroaryl are as defined above,
(M) xe2x80x94RN-arylxe2x80x94SO2xe2x80x94RN-aryl where xe2x80x94RN-aryl is as defined above,
(N) xe2x80x94RN-heteroaryl-COxe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(O) xe2x80x94RN-heteroarylxe2x80x94SO2xe2x80x94RN-heteroaryl where RN-heteroaryl is as defined above,
(P) xe2x80x94RN-arylxe2x80x94Oxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-aryl is as defined above,
(Q) xe2x80x94RN-arylxe2x80x94Sxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-aryl is as defined above,
(R) xe2x80x94RN-heteroarylxe2x80x94Oxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-heteroaryl is as defined above, or
(S) xe2x80x94RN-heteroarylSxe2x80x94(C1-C8 alkyl)-xcfx86 where RN-heteroaryl is as defined above,
(II) Axe2x80x94XNxe2x80x94 where XN is xe2x80x94COxe2x80x94,
wherein A is
(A) xe2x80x94Txe2x80x94Exe2x80x94(Q)mxe2x80x2,
(1) where xe2x80x94T is: 
where
(a) x=1 when y=1 and x=2 when y=0,
(b) m is 0, 1, 2 or 3,
(c) the values of x and y vary independently on each carbon when m is 2 and 3, and
(d) Rxe2x80x3 varies independently on each carbon and is H, (C1-C2) alkyl, phenyl, or phenyl(C1-C3)alkyl;
(2) xe2x80x94E is
(a) C1-C5 alkyl, but only if mxe2x80x2 does not equal 0,
(b) methylthioxy(C2-C4)alkyl,
(c) an aryl group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,
(d) a heterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused,
(e) a mono or fused ring cycloalkyl group having 5 to 10 carbon atoms,
(f) biphenyl,
(g) diphenyl ether,
(h) diphenylketone,
(i) phenyl(C1-C8)alkyloxyphenyl, or
(j) C1-C6 alkoxy;
(3) xe2x80x94Q is
(a) C1-C3 alkyl,
(b) C1-C3 alkoxy,
(c) C1-C3 alkylthioxy,
(d) C1-C6 alkylacylamino,
(e) C1-C6 alkylacyloxy,
(f) amido (including primary, C1-C6 alkyl and phenyl secondary and tertiary amino moieties),
(g) C1-C6 alkylamino
(h) phenylamino,
(i) carbamyl (including C1-C6 alkyl and phenyl amides and esters),
(j) carboxyl (including C1-C6 alkyl and phenyl esters),
(k) carboxy(C2-C5)alkoxy,
(l) carboxy(C2-C5)alkylthioxy,
(m) heterocyclylacyl,
(n) heteroarylacyl, or
(o) hydroxyl;
(4) mxe2x80x2is 0, 1, 2 or 3;
(B) xe2x80x94E(Q)mxe2x80x3 wherein E and xe2x80x94Q are as defined as above and mxe2x80x3 is 0, 1, 2, or 3;
(C) xe2x80x94Txe2x80x94E wherein xe2x80x94E and xe2x80x94Q are as defined as above; or
(D) xe2x80x94E wherein xe2x80x94E is as defined as above;
(III) xe2x80x94COxe2x80x94(C1-C6 alkyl) where alkyl is unsubstituted or substituted with one or two:
(A) xe2x80x94OH,
(B) xe2x80x94C1-C6 alkoxy,
(C) xe2x80x94C1-C6 thioalkoxy,
(D) xe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is xe2x80x94H, C1-C6 alkyl or -xcfx86,
(E) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) xe2x80x94COxe2x80x94RN-4 where RN-4 is as defined above,
(G) xe2x80x94SO2xe2x80x94(C1-C8 alkyl),
(H) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) xe2x80x94NHxe2x80x94COxe2x80x94(C1-C6 alkyl),
(J) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is as defined above,
(K) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) xe2x80x94RN-4 where RN-4 is as defined above,
(M) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(N) xe2x80x94Oxe2x80x94COxe2x80x94NRN-8RN-8 where the RN-8 is the same or different and are as defined above, or
(O) xe2x80x94Oxe2x80x94(C1-C5 alkyl)-COOH,
(IV) xe2x80x94COxe2x80x94(C1-C3 alkyl)xe2x80x94Oxe2x80x94(C1-C3 alkyl) where alkyl is unsubstituted or substituted with one or two
(A) xe2x80x94OH,
(B) xe2x80x94C1-C6 alkoxy,
(C) xe2x80x94C1-C6 thioalkoxy,
(D) xe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is xe2x80x94H, C1-C6 alkyl or -xcfx86,
(E) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) xe2x80x94COxe2x80x94RN-4 where RN-4 is as defined above,
(G) xe2x80x94SO2xe2x80x94(C1-C8 alkyl),
(H) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) xe2x80x94NHxe2x80x94COxe2x80x94(C1-C6 alkyl),
(J) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is as defined above,
(K) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) xe2x80x94RN-4 where RN-4 is as defined above,
(M) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(N) xe2x80x94Oxe2x80x94COxe2x80x94NRN-8RN-8 where the RN-8 are the same or different and are as defined above, or
(O) xe2x80x94Oxe2x80x94(C1-C5 alkyl)-COOH,
(V) xe2x80x94COxe2x80x94(C1-C3 alkyl)xe2x80x94Sxe2x80x94(C1-C3 alkyl) where alkyl is unsubstituted or substituted with one or two
(A) xe2x80x94OH,
(B) xe2x80x94C1-C6 alkoxy,
(C) xe2x80x94C1-C6 thioalkoxy,
(D) COxe2x80x94Oxe2x80x94RN-8 where RN-8 is xe2x80x94H, C1-C6 alkyl or -xcfx86,
(E) xe2x80x94COxe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(F) xe2x80x94COxe2x80x94RN-4 where RN-4 is as defined above,
(G) xe2x80x94SO2xe2x80x94(C1-C8 alkyl),
(H) xe2x80x94SO2xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(I) xe2x80x94NHxe2x80x94COxe2x80x94(C1-C6 alkyl),
(J) xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94RN-8 where RN-8 is as defined above,
(K) xe2x80x94NRN-2RN-3 where RN-2 and RN-3 are the same or different and are as defined above,
(L) xe2x80x94RN-4 where RN-4 is as defined above,
(M) xe2x80x94Oxe2x80x94COxe2x80x94(C1-C6 alkyl),
(N) xe2x80x94Oxe2x80x94COxe2x80x94NRN-8RN-8 where the RN-8 are the same or different and are as defined above, or
(O) xe2x80x94Oxe2x80x94(C1-C5 alkyl)-COOH,
(VI) xe2x80x94COxe2x80x94CH(xe2x80x94(CH2)0-2xe2x80x94Oxe2x80x94RN-1 0)xe2x80x94(CH2)0-2xe2x80x94RN-aryl/RN-heteroaryl) where RN-aryl and RN-heteroaryl are as defined above, where RN-10 is:
(A) xe2x80x94H,
(B) C1-C6 alkyl,
(C) C3-C7 cycloalkyl,
(D) C2-C6 alkenyl with one double bond,
(E) C2-C6 alkynyl with one triple bond,
(F) R1-aryl where R1-aryl is as defined above, or
(G) RN-heteroaryl where RN-heteroaryl is as defined above.
It is preferred that RN is RN-1xe2x80x94XNxe2x80x94 where XN is xe2x80x94COxe2x80x94, where RN1, is RN-aryl where RN-aryl is phenyl substituted with one xe2x80x94COxe2x80x94NRN-2 RN-3 where the substitution on phenyl is 1,3-,
RN-1 xe2x80x94XNxe2x80x94 where XN is xe2x80x94COxe2x80x94, where RN-1 is RN-aryl where RN-aryl is phenyl substituted with one C1 alkyl and with one xe2x80x94COxe2x80x94NRN-2RN-3 where the substitution on the phenyl is 1,3,5-, or
RN-1 xe2x80x94XNxe2x80x94 where XN is xe2x80x94COxe2x80x94, where RN-1 is RN-heteroaryl where RN-heteroaryl is substituted with one xe2x80x94COxe2x80x94NRN-2RN-3. It is further preferred that RN-2 and RN-3 are the same and are C3 alkyl.
It is further preferred that:
RN-1 xe2x80x94XNxe2x80x94 where XN is xe2x80x94COxe2x80x94, where RN-1 is RN-aryl where RN-aryl is phenyl substituted with one xe2x80x94COxe2x80x94NRN-2RN-3 where the substitution on phenyl is 1,3-,
RN-1 xe2x80x94XNxe2x80x94 where XN is xe2x80x94COxe2x80x94, where RN-1 is RN-aryl where RN-aryl is phenyl substituted with one C1 alkyl and with one xe2x80x94COxe2x80x94NRN-2RN-3 where the substitution on the phenyl is 1,3,5-.
It is preferred that XN is (A) xe2x80x94COxe2x80x94 and (B) xe2x80x94SO2xe2x80x94; it is more preferred that XN be xe2x80x94COxe2x80x94.
The nitrogen-acylation of primary amines to produce secondary amides is one of the oldest known reactions. The amide forming agents, (RN-1 xe2x80x94XN)2O or RN-1 xe2x80x94XNxe2x80x94X2 or RN-1 xe2x80x94XNxe2x80x94OH  are known to those skilled in the art and are commercially available or can be readily prepared from known starting materials by methods known in the literature. X2 includes xe2x80x94Cl, xe2x80x94Br; it is preferred that X2 is xe2x80x94Cl. It is preferred to use an isophthalic acid acylating agent of the formula RN-2RN-3Nxe2x80x94CO-xcfx86- COxe2x80x94 or a methylisophthalic acid acylating agent RN-2RN-3Nxe2x80x94COxe2x80x94(CH3xe2x80x94)xcfx86- COxe2x80x94 where the substitution is 5-methyl-1,3-isophthalic acid. The more preferred 5-methyl-1,3-isophthalic acid is 3-[(N,N-dipropylamino)carbonyl]-5-methylbenzoic acid. These compounds are preferably prepared as set forth as follows. An ester, preferably the methyl ester of isophthalate or methyl 5-methyl-1,3-isophthalate is dissolved in a THF/DMF mixture. 1,1xe2x80x2-Carbonyldiimidazole is then added at 0-100xc2x0. Next the desired amine (H-NRN-2RN3) is added. After stirring at 0-100xc2x0 the reaction mixture is partitioned between a saturated aqueous solution with a pH of 3 to 9 and a water immiscible organic solvent. The aqueous layer is separated and extracted twice more with the organic solvent. The organic extracts are combined and then washed with an aqueous solution and dried. Filtration of the drying agent and removal of solvents by reduced pressure gives crude ester of the desired RN-2RN-3Nxe2x80x94CO-xcfx86-COxe2x80x94Oxe2x80x94CH3 or a methylisophthalic acid acylating agent RN-2RN-3Nxe2x80x94COxe2x80x94(CH3xe2x80x94)xcfx86-COxe2x80x94Oxe2x80x94CH3. Purification of the ester can be achieved via chromatography on silica gel eluting with a suitable solvent The isophthalate ester or methylisophthalate ester of the mono-alkyl or di-alkyl amide is then treated with an aqueous solution of base such as alkali hydroxide in a minimum amount of THF/methanol/water and stirred at 20-70xc2x0 with monitoring. The solvents are removed under reduced pressure and subsequently partitioned between water and a water immiscible organic solvent. The aqueous phase is separated and extracted once more with a water immiscible organic solvent. The aqueous phase was then acidified to pH xe2x89xa63. The mixture obtained is then extracted three times with ethyl acetate. These combined organic extracts are then dried. The drying agent is removed by filtration and the organic solvent remove under reduced pressure to gave crude product. The crude mono- or di-alkyl amide isophthalate/methylisophthalate is used as such in the next reaction with the amine (X) to produce the lactone (XI).
When it is desired to produce a primary amide, RN-2 and RN-3 are both xe2x80x94H, the following procedure is preferred. An ester of isophthalate or methyl 5-methyl-1,3-isophthalate is dissolved in a THF/DMF mixture. CDI is then added at 0-100xc2x0. Ammonia gas is then bubbled into the mixture with monitoring. The reaction is cooled to 0xc2x0 for the duration of the ammonia addition. The reaction is left stirring under a balloon of ammonia at 0-100xc2x0 with monitoring. The reaction is partitioned between a aqueous solution with a pH of 3 to 9 and a water immiscible organic solvent. The phases are separated and the aqueous phase is extracted twice more with a water immiscible organic solvent. The organic extracts are washed with an aqueous solution and dried. Removal of solvents under reduced pressure gives crude ester of the desired H2Nxe2x80x94CO-xcfx86-COxe2x80x94O(Alkyl) or a methylisophthalic acid acylating agent H2Nxe2x80x94COxe2x80x94(CH3xe2x80x94)xcfx86-COxe2x80x94O(Alkyl). Purification of the crude ester can be achieved via chromatography on silica gel eluting with isopropanol/chloroform. The isophthalate ester or methylisophthalate ester of the primary amide is then treated with an aqueous solution of base such as alkali hydroxide in a minimum amount of THF/methanol/water and stirred at 0-100xc2x0 with monitoring. The solvents are removed under reduced pressure and subsequently partitioned between water and a water immiscible organic solvent. The aqueous phase is separated and extracted once more with a water immiscible organic solvent. The aqueous phase is then acidified until pH xe2x89xa63. The mixture obtained is then extracted three times with a water immiscible organic solvent. These combined organic extracts are dried and the organic solvent removed under reduced pressure to gave crude product. The primary amide isophthalate/methylisophthalate is used as such in the next reaction with (X) to produce (XI).
When it is desired that the amine be cyclized to be a group such as morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl, etc the following procedure is followed. An ester of isophthalate or methyl 5-methyl-1,3-isophthalate is dissolved in a suitable organic solvent and a catalytic amount or DMF is added. The mixture is cooled to xe2x88x9220xc2x0 to below rt and then oxalyl chloride is added. The mixture is stirred with monitoring and the solvents removed under reduced pressure. The acid chloride is left under vacuum overnight. The crude acid chloride is dissolved in a suitable organic solvent and cooled to xe2x88x9220xc2x0 to below rt before the addition of the cyclic amine and N-methyl piperidine. The reaction mixture is stirred at xe2x88x9220xc2x0 to below rt with monitoring before the solvents are removed. The residue is diluted with water and water immiscible organic solvent and the phases are separated. The aqueous phase is extracted twice more with water immiscible organic solvent, and the combined organic extracts are washed with an aqueous solution and dried. Removal of solvents under reduced pressure gives the crude product. The crude cyclicamide is then treated with an aqueous base such as alkali hydroxide a minimum amount of THF/methanol/water and stirred overnight at 0-100xc2x0. The solvents are removed under reduced pressure and subsequently partitioned between water and a water immiscible organic solvent. The aqueous phase is extracted once more with a water immiscible organic solvent. Removal of water from the aqueous phase under reduced pressure gives the desired cyclic amide product.
The lactone (XI) may then be reacted with the appropriately substituted C-terminal amine, RCxe2x80x94NH2 by means known to those skilled in the art which opens the lactone to produce the desired hydroxyethylene end product (XII). The substituted C-terminal amines, RCxe2x80x94NH2 of this invention are commercially available or are known to those skilled in the art and can be readily prepared from known compounds. RC includes:
(I) xe2x80x94(C1-C10)alkyl-K1-3 in which:
(A) the alkyl chain is unsubstituted or substituted with one xe2x80x94OH,
(B) the alkyl chain is unsubstituted or substituted with one C1-C6 alkoxy unsubstituted or substituted with 1-5 xe2x80x94F,
(C) the alkyl chain is unsubstituted or substituted with one xe2x80x94O-xcfx86,
(D) the alkyl chain is unsubstituted or substituted with 1, 2, 3, 4 or 5 xe2x80x94F,
(E) the alkyl chain is unsubstituted or substituted with a combination of up to three atoms of oxygen and sulfur each such atom replacing one carbon,
(F) each K is:
(1) H,
(2) C1-C3 alkyl,
(3) C1-C3 alkoxy,
(4) C1-C3 alkylthioxy,
(5) C1-C6 alkylacylamino,
(6) C1-C6 alkylacyloxy,
(7) amido
(8) C1-C6 alkylamino
(9) phenylamino,
(10) carbamyl
(11) carboxyl
(12) carboxy(C2-C5)alkoxy,
(13) carboxy(C2-C5)alkylthioxy,
(14) heterocyclylacyl,
(15) heteroarylacyl,
(16) amino unsubstituted or substituted with C1-C6 alkyl,
(17) hydroxyl, or
(18) carboxyl methyl ester;
(II)xe2x80x94(CH2)0-3xe2x80x94J-[(xe2x80x94(CH2)0-3-K]1-3 where K is as defined above and J is:
(A) a 5 to 7 atom monocyclic aryl group,
(B) a 8 to 12 atom multicyclic aryl group,
(C) a 5 to 7 atom heterocyclic group,
(D) a 8 to 12 atom multicyclic heterocyclic group, or
(E) a 5 to 10 atom monocyclic or multicyclic cycloalkyl group;
(III) xe2x80x94(CH2)0-3xe2x80x94(C3-C7) cycloalkyl where cycloalkyl can be unsubstituted or substituted with one, two or three
(A) C1-C3 alkyl unsubstituted or substituted with 1, 2, 3, or 4 xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, or xe2x80x94I,
(B) xe2x80x94COxe2x80x94OH,
(C) xe2x80x94COxe2x80x94Oxe2x80x94(C1-C4 alkyl),
(D)xe2x80x94OH, or
(E) C1-C6 alkoxy,
(IV) xe2x80x94(CH2)2-6xe2x80x94OH,
(V) xe2x80x94(CRC-xRC-y)0-4xe2x80x94RC-x where RC-x and RC-y are xe2x80x94H, C1-C4 alkyl and xcfx86- and RC-aryl is the same as RN-aryl,
(VI) xe2x80x94(CH2)0-4xe2x80x94RC-heteroaryl where RC-heteroaryl is:
(A) pyridinyl,
(B) pyrimidinyl,
(C) quinolinyl,
(D) indenyl,
(E) indanyl,
(F) benzothiophenyl,
(G) indolyl,
(H) indolinyl,
(I) pyridazinyl,
(J) pyrazinyl,
(K) isoindolyl,
(L) isoquinolyl,
(M) quinazolinyl,
(N) quinoxalinyl,
(O) phthalazinyl,
(P) isoxazolyl,
(Q) pyrazolyl,
(R) indolizinyl,
(S) indazolyl,
(T) benzothiazolyl,
(U) benzimidazolyl,
(V) benzofuranyl,
(W) furanyl,
(X) thienyl,
(Y) pyrrolyl,
(Z) oxadiazolyl,
(AA) thiadiazolyl,
(BB) triazolyl,
(CC) tetrazolyl,
(DD) 1,4-benzodioxan
(EE) purinyl,
(FF) oxazolopyridinyl,
(GG) imidazopyridinyl,
(HH) isothiazolyl,
(II) naphthyridinyl,
(JJ) cinnolinyl,
(KK) carbazolyl,
(LL) xcex2-carbolinyl,
(MM) isochromanyl,
(NN) chromanyl,
(OO) furazanyl,
(PP) tetrahydroisoquinoline,
(QQ) isoindolinyl,
(RR) isobenzotetrahydrofuranyl,
(SS) isobenzotetrahydrothienyl,
(TT) isobenzothiophenyl,
(UU) benzoxazolyl, or
(VV) pyridopyridinyl,
(VI ) xe2x80x94(CH2)0-4xe2x80x94RC-heterocycle where RC-heterocycle is the same as R1-heterocycle,
(VIII) xe2x80x94C(RC-1)(RC-2)xe2x80x94COxe2x80x94NHxe2x80x94RC-3 where RC-1 and RC-2 are the same or different and are:
(A) xe2x80x94H,
(B) xe2x80x94C1-C6 alkyl,
(C) xe2x80x94(C1-C4 alkyl)-RCxe2x80x2-aryl where RCxe2x80x2-aryl is as defined above for R1-aryl,
(D) xe2x80x94(C1-C4 alkyl)-RC-heteroaryl where RC-heteroaryl is as defined above,
(E) xe2x80x94(C1-C4 alkyl)-RC-heterocycle where RC-heterocycle is as defined above,
(F) xe2x80x94RC-heteroaryl where RC-heteroaryl is as defined above,
(G) xe2x80x94RC-heterocycle where RC-heterocycle is as defined above,
(H) xe2x80x94(CH2)1-4xe2x80x94OH,
(I) xe2x80x94(CH2)1-4xe2x80x94RC-4xe2x80x94(CH2)1-4xe2x80x94RCxe2x80x2-aryl where RC-4 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94NHRC-5xe2x80x94 where RC-5 is C1-C6 alkyl, and where RCxe2x80x2-aryl is as defined above,
(J) xe2x80x94(CH2)1-4xe2x80x94RC-4xe2x80x94(CH2)1-4xe2x80x94RC-heteroaryl where RC-4 and RC-heteroaryl are as defined above, or
(K) xe2x80x94RCxe2x80x2-aryl where RCxe2x80x2-aryl is as defined above,
and where RC-3 is:
(A) xe2x80x94H,
(B) xe2x80x94C1-C6 alkyl,
(C) xe2x80x94RCxe2x80x2-aryl where RCxe2x80x2-aryl is as defined above,
(D) xe2x80x94RC-heteroaryl where RC-heteroaryl  is as defined above,
(E) xe2x80x94RC-heterocycle where RC-heterocycle  is as defined above,
(F) xe2x80x94(C1-C4 alkyl)-RCxe2x80x2-aryl where RCxe2x80x2-aryl is as defined above,
(G) xe2x80x94(C1-C4 alkyl)-RC-heteroaryl where RC-heteroaryl is as defined above, or
(H) xe2x80x94(C1xe2x80x94C4 alkyl)-RC-heterocycle where RC-heterocycle is as defined above,
(IX) xe2x80x94CH(xcfx86)2,
(X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring where heteroaryl is as defined above and phenyl and heteroaryl are unsubstituted or substituted with one, two or three:
(A) C1-C3 alkyl,
(B) xe2x80x94CF3,
(C) xe2x80x94F, Cl, xe2x80x94Br and xe2x80x94I,
(D) C1-C3 alkoxy,
(E) xe2x80x94OCF3,
(F) xe2x80x94NH2,
(G) xe2x80x94OH, or
(H) xe2x80x94Cxe2x89xa1N,
(XI) xe2x80x94CH2xe2x80x94Cxe2x89xa1CH;
(XII) xe2x80x94(CH2)0-4xe2x80x94CHRC-5xe2x80x94(CH2)0-1-xcfx86 where RC-5 is:
(A) xe2x80x94OH, or
(B)xe2x80x94CH2xe2x80x94OH;
(XIII) xe2x80x94CH(-xcfx86)-COxe2x80x94O(C1-C3 alkyl);
(XIV) xe2x80x94CH(xe2x80x94CH2xe2x80x94OH)xe2x80x94CH(xe2x80x94OH)-xcfx86-NO2;
(XV) xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94OH;
(XVI) xe2x80x94CH2xe2x80x94NHxe2x80x94CH2xe2x80x94CH(xe2x80x94Oxe2x80x94CH2xe2x80x94CH3)2;
(XVII) xe2x80x94(C2-C8) alkynyl; or
(XVIII) xe2x80x94H.
Typically, RC is:
(I)xe2x80x94C1-C8 alkyl,
(II) xe2x80x94(CH2)0-3xe2x80x94(C3-C7) cycloalkyl,
(III) xe2x80x94(CH2)0-3xe2x80x94OH,
(IV) xe2x80x94(CRC-xRC-y)0-4xe2x80x94RC-aryl,
(V) xe2x80x94(CH2)0-4xe2x80x94RC-heteroaryl,
(VI) xe2x80x94(CH2)0-4xe2x80x94RC-heterocycle,
(VII) xe2x80x94C(RC-1)(RC-2)xe2x80x94COxe2x80x94NHxe2x80x94RC-3,
(IX) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring where heteroaryl is as defined above and phenyl and heteroaryl are unsubstituted or substituted with one or two:
(A) C1-C3 alkyl,
(B) xe2x80x94CF3,
(C) xe2x80x94F, Cl, xe2x80x94Br or xe2x80x94I,
(D) C1-C3 alkoxy,
(E) xe2x80x94OCF3, or
(XVI) xe2x80x94H.
It is preferred that RC is:
(II) xe2x80x94(CH2)0-3xe2x80x94(C3-C7) cycloalkyl,
(IV) xe2x80x94(CRC-xRC-y)0-4xe2x80x94RC-aryl,
(V) xe2x80x94(CH2)0-4xe2x80x94RC-heteroaryl,
(VI) xe2x80x94(CH2)0-4xe2x80x94RC-heterocycle,
(VII) xe2x80x94C(RC-1)(RC-2)xe2x80x94COxe2x80x94NHxe2x80x94RC-3, or
(IX) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring.
It is more preferred that RC is:
(IV) xe2x80x94(CRC-xRC-y)0-4xe2x80x94RC-aryl,
(V) xe2x80x94(CH2)0-4xe2x80x94RC-heteroaryl,
(VI) xe2x80x94(CH2)0-4xe2x80x94RC-heterocycle, or
(IX) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ring.
It is most preferred that RC is:
(IV) xe2x80x94(CRC-xRC-y)0-4xe2x80x94RC-aryl where RC-aryl is phenyl,
(V) xe2x80x94CH2xe2x80x94RC-heteroaryl,
(VI) xe2x80x94CH2xe2x80x94RC-heterocycle, or
(IX) -cyclohexyl ring fused to a phenyl ring. Further, it is preferred that when RC is phenyl, it is substituted in the 3-position or 3,5-positions.
Suitable reaction conditions for opening the lactone (XI) to produce the desired hydroxyethylene end product (XII) include those of the AlMe3-mediated coupling reaction disclosed in the literature procedure of S. F. Martin et al., Tetrahedron Lett. 1998, 39, 1517-1520. When the substituted C-terminal amine is a 1-amino-3,5-cis-dimethyl cyclohexyldicarboxylate it is preferrably prepared as follows. To dimethyl-5-isophthalate in acetic acid and methanol, is added rhodium in alumina in a high-pressure bottle. The bottle is saturated with hydrogen at 55 psi and shaken for one week of time. The mixture is then filtered through a thick layer of celite cake and rinsed with methanol three times, the solvents are removed under reduced pressure (with heat) to give a concentrate. The concentrate is triturated with ether and filtered again to give the desired C-terminal amine. When the substituted C-terminal amine is 1-amino-3,5-cis-dimethoxy cyclohexane it is preferably following the general procedure above and making non-critical variations but starting with 3,5-dimethoxyaniline. When the substituted C-terminal amine is an aminomethyl group where the substituent on the methyl group is an aryl group, for example NH2xe2x80x94CH2xe2x80x94RC-aryl, and NH2xe2x80x94CH2xe2x80x94RC-aryl is not commercially available it is preferrably prepared as follows. A suitable starting material is the (appropriately substituted) aralkyl compound. The first step is bromination of the alkyl substitutent via methods known to those skilled in the art, see for example R. C. Larock in Comprehensive Organic Transformations, VCH Publishers, 1989, p. 313. Next the alkyl halide is reacted with azide to produce the aryl-(alkyl)-azide. Last the azide is reduced to the corresponding amine by hydrogen/catalyst to give the C-terminal amine of formula NH2xe2x80x94CH2xe2x80x94RC-aryl.
CHART B, as defined within, sets forth a process for production of the amide (VII). Preparation of the amide (VIII) starts with the reaction of an appropriate amino-indanol (XIV) with an appropriate haloketone (XII) to afford the hydroxy indane (XV). The amino-indanol (XIV) and haloketone (XII) are well known to those skilled in the art or can be readily prepared from known compounds by methods well known to those skilled in the art. The X substituent of the haloketone is typically F, Cl, Br, or I.
Preferably X is Cl. For the amino haloketone (XII), R2 is:
(I) xe2x80x94H,
(II) C1-C6 alkyl, or
(III) xe2x80x94(CH2)0-4xe2x80x94R2-1 where R2-1 is (C3-C6)cycloalkyl, R1-aryl or R1-heteroaryl where R1-aryl and R1-heteroaryl are as defined above,
Certain hydroxyethylene compounds of formula (XII) contain acidic functionality capable of forming base addition salts. Additionally, certain hydroxyethylene compounds of formula (XII) contain basic functionality capable of forming acid addition salts. For example, certain hydroxyethylene compounds of formula (XII) are amines and as such form salts when reacted with acids. Pharmaceutically acceptable salts are preferred over the corresponding hydroxyethylene compounds of formula (XII) since they produce compounds which are more water soluble, stable and/or more crystalline. Pharmaceutically acceptable salts are any salt which retains the activity of the parent compound and does not impart any deleterious or undersirable effect on the subject to whom it is administered and in the context in which it is administered. Pharmaceutically acceptable salts include salts of both inorganic and organic acids. The preferred pharmaceutically acceptable salts include salts of the following acids: hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, citric, methanesulfonic, CH3xe2x80x94(CH2)n1xe2x80x94COOH where n1 is 0 thru 4, HOOCxe2x80x94(CH2)n1xe2x80x94COOH where n is as defined above, HOOCxe2x80x94CHxe2x95x90CHxe2x80x94COOH, and "PHgr"-COOH. Additionally, preferred pharmaceutically acceptable salts include salts of the following bases: triethanolamine, N-methylglucamine, diethanolamine, ethanolamine, tris(hydroxymethyl)aminomethane (TRIS), ammonia, and carbonate, bicarbonate, phosphonate, or hydroxide salts of an alkali or alkaline earth metal. For other acceptable salts, see Int. J. Pharm., 33, 201-217 (1986).
Preferred hydroxyethylene compounds of formula (XII), include, for example, N-[(1S, 2S, 4R)-1-(3,5-Difluorobenzyl)-4-(syn, syn)-(3,5 dimethoxycyclohexylcarbamoyl)-2-hydroxyhexyl]-N,N-dipropylisophathalamide, 6-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2xe2x80x94(R)-ethyl-4-(S) -hydroxyhexanoylamino]-hexanoic acid, 5-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2xe2x80x94(R)-ethyl-4-(S)-hydroxyhexanoylamino]-pentanoic acid, 4-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2xe2x80x94(R)-ethyl-4-(S)-hydroxyhexanoylamino]-butyric acid, 3-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2xe2x80x94(R)-ethyl-4-(S)-hydroxyhexanoylamino]-propionic acid, 8-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2xe2x80x94(R)-ethyl-4-(S)-hydroxyhexanoylamino]-octanoic acid, 8-[6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2xe2x80x94(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-octanoic acid methyl ester, N-[4xe2x80x94(R)-Butylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4xe2x80x94(R)-isobutylcarbamoyl-hexyl]-N,N-dipropyl-isophthalamide, N-[4xe2x80x94(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[4xe2x80x94(R)xe2x80x94(Cyclohexylmethyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4xe2x80x94(R)-(piperidine-1-carbonyl)-hexyl]-N,N-dipropyl-isophthalamide, N-[1-(S-(3,5-Difluoro-benzyl)-4xe2x80x94(R)-(2-dimethylamino-ethylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[4xe2x80x94(R)-(Butyl-methyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, N-[1-(5S-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4xe2x80x94(R)-(3-hydroxy-propylcarbamoyl)-hexyl]-N,N-dipropyl-isophthalamide, 4-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2xe2x80x94(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid methyl ester, N-[1-(5-(3,5-Difluoro-benzyl)-4xe2x80x94(R)-(3-dimethylamino-propylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2xe2x80x94(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2xe2x80x94(R)-methyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(5)-hydroxy-2xe2x80x94(R)-propyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxyl-2xe2x80x94(R)-isobutyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([2xe2x80x94(R)-Benzyl-6-(3,5-difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2xe2x80x94(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2xe2x80x94(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid methyl ester, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4xe2x80x94(R)-(2-morpholin-4-yl-ethylcarbamoyl)-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4xe2x80x94(R)-isobutylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[4xe2x80x94(R)-(2-Diethylamino-ethylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4xe2x80x94(R)-[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-pentyl)-5-methyl-N,N-dipropyl-isophthalamide, N-[4xe2x80x94(R)-(Adamantan-2-ylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4xe2x80x94(R)-methyl-5-morpholin-4-yl-5-oxo-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[4xe2x80x94(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-4xe2x80x94(R)-(4-fluoro-benzylcarbamoyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4xe2x80x94(R)-phenethylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide, N-[1-(S)-(3,5-Difluoro-benzyl)-4xe2x80x94(R)-[(furan-2-ylmethyl)-carbamoyl]-2-(S)-hydroxy-pentyl)-5-methyl-N,N-dipropyl-isophthalamide, or N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4xe2x80x94(R)-(prop-2-ylcarbamoyl)-pentyl]-5-methyl-N,N-dipropyl-isophthalamide.
Additional preferred hydroxyethylene compounds of formula (XII) include, for example those of the following formulae: 
Most preferred hydroxyethylene compounds of formula (XII), include, for example, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2xe2x80x94(R)-propyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid.
6-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2xe2x80x94(R)-ethyl-4-(S)-hydroxyhexanoylamino]-hexanoic acid,
8-[6-(3,5-Difluoro-phenyl)-5-(-(3-dipropylcarbamoyl-benzoylamino)-2xe2x80x94(R)-ethyl-4-(S)-hydroxy-hydroxyhexanoylamino]-octanoic acid methyl ester,
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2xe2x80x94(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid
4-(anti)-([2xe2x80x94(R)-Benzyl-6-(3,5-difluoro-phenyl)-5-(s)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid, and
4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2xe2x80x94(R)-methyl-hexanoylamino]-methyl)-cyclohexanecarboxylic acid.
The hydroxyethylene compounds of formula (XII), and pharmaceutically acceptable salts thereof, are useful for treating humans suffering from Alzheimer""s disease, for helping prevent or delay the onset of Alzheimer""s disease, for treating patients with MCI (mild cognitive impairment) and preventing or delaying the onset of Alzheimer""s disease in those who would progress from MCI to AD, for treating Down""s syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobal hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson""s disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type Alzheimer""s disease. It is preferred the the disease is Alzheimer""s disease.
When treating these diseases, the hydroxyethylene compounds of formula (XII) can either be used individually or in combination as is best for the patient.
With regard to these diseases the term xe2x80x9ctreatingxe2x80x9d means that the hydroxyethylene compounds of formula (XII) can be used in humans with existing disease. The hydroxyethylene compounds of formula (XII) will not necessarily cure the patient who has the disease but will delay or slow the progression of the disease thereby giving the individual a more useful life span.
The term xe2x80x9cpreventingxe2x80x9d means that if the compounds of the present invention are administered to those who do not now have the disease but who would normally get the disease or be at increased risk for the disease, they will not get the disease. In addition, xe2x80x9cpreventingxe2x80x9d also includes delaying the development of the disease in an individual who will ultimately get the disease or would be at risk for the disease. By delaying the onset of the disease, the hydroxyethylene compounds of formula (XII) have prevented the individual from getting the disease during the period in which the individual would normally have gotten the disease or reduce the rate of development of the disease or some of its effects but for the administration of the hydroxyethylene compounds of formula (XII) up to the time the individual ultimately gets the disease. Preventing also includes administration of the compounds of the invention to those individuals thought to be predisposed to the disease due to familial history and/or due to the presence of one or more biological markers for the disease such as a known genetic mutation of APP or by analysis of APP cleavage products in body tissues or fluids.
In treating or preventing the above diseases the hydroxyethylene compounds of formula (XII) are administered in a therapeutically effective amount. The therapeutically effective amount will vary depending on the particular compound used and the route of administration as is known to those skilled in the art.
In treating a patient with any of the diagnosed above conditions a physician may administer hydroxyethylenes of formula (XII) immediately and continue indefinitely.
In treating patients who do not at the present have Alzheimer""s disease, but who are believed to be at substantial risk for Alzheimer""s disease, the physician should start treatment when the patient first experiences early pre-Alzheimer""s symptoms such as, memory or cognitive problems associated with aging. In addition, there are some patients who may be diagnosed with Alzheimer""s through the detection of the genetic marker APOE4 or other biological indicators that are predictive for Alzheimer""s disease. In these situations, even though the patient does not have symptoms of the disease, the administration of the hydroxyethylene compounds of formula (XII) may be started before they appear and treatment continued indefinitely to prevent or delay the outset of the disease.
The hydroxyethylene compounds of formula (XII) can be administered orally, parenterally (IV, IM, depo-IM, SQ and depo-SQ), sublingually, intranasally (inhalation), intrathecally, topically and rectally. The invention here is the novel hydroxyethylene compounds of formula (XII). Dosage forms known to those skilled in the art are suitable for delivery of the novel hydroxyethylene compounds of formula (XII).
Hydroxyethylene compounds of formula (XII) may be administered enterally or parenterally. When administered orally, hydroxyethylene compounds of formula (XII) can be administered in usual dosage forms for oral administration as is well known to those skilled in the art. These dosage forms include the usual solid unit dosage forms of tablets and capsules as well as liquid dosage forms such as solutions, suspensions and elixirs. When the solid dosage forms are used, it is preferred that they be of the sustained release type so that the hydroxyethylene compounds of formula (XII) need to be administered only once or twice daily.
The oral dosage forms are administered to the patient 1, 2, 3, or 4 times daily. It is preferred that the hydroxyethylene compounds of formula (XII) be administered either three or fewer times, more preferably once or twice daily. Hence, it is preferred that the hydroxyethylene compounds of formula (XII) be administered in oral dosage form. It is preferred that whatever oral dosage form is used, that it be designed so as to protect the hydroxyethylene compounds of formula (XII) from the acidic environment of the stomach. Enteric coated tablets are well known to those skilled in the art. In addition, capsules filled with small spheres each coated to protect from the acidic stomach, are also well known to those skilled in the art. When administered orally the therapeutically effective amount is from about 0.1 mg/day to about 1,000 mg/day. It is preferred that the oral dosage is from about 1 mg/day to about 100 mg/day. It is more preferred that the oral dosage is from about 5 mg/day to about 50 mg/day. It is understood that while a patient may be started on one dose, that dose may have to be varied over time as the patient""s condition changes.
Hydroxyethylene compounds of formula (XII) may also be advantageously delivered in a nano crystal dispersion formulation. Preparation of such formulations is described in U.S. Pat. No. 5,145,684. And nano crystalline dispersions of, for example, HIV protease inhibitors and their method of use are described in U.S. Pat. No. 6,045,829. The nano crystalline formulations typically afford greater bioavailability of drug compounds.
In addition, the hydroxyethylene compounds of formula (XII) can be administered parenterally. When admninistered parenterally they can be administered IV, IM, depo-IM, SC or depo-SC. When administered parenterally, the hydroxyethylene compounds of formula (XII) should deliver a therapeutically effective amount about 0.5 to about 100 mg/day, preferably from about 5 to about 50 mg daily. When a depo formulation is used for injection once a month or once every two weeks, the dose should be about 0.5 mg/day to about 50 mg/day or on a monthly amount the dose for one month should be from about 15 mg to about 1,500 mg. Because of the forgetfulness of the patients with Alzheimer""s disease, it is preferred that the parenteral dosage form be a depo-IM injection.
The hydroxyethylene compounds of formula (XII) can be given sublingually. When given sublingually, the hydroxyethylene compounds of formula (XII) should be given one thru four times daily in the same amount as for IM administration.
The hydroxyethylene compounds of formula (XII) can be given intranasally. When given by this route of administration, the appropriate dosage forms are a nasal spray or dry powder as is known to those skilled in the art. The dosage of the hydroxyethylene compounds of formula (XII) for intranasal administration is the same as for IM administration.
The hydroxyethylene compounds of formula (XII) can be given intrathecally. When given by this route of administration the appropriate dosage form can be a parenteral dosage form as is known to those skilled in the art. The dosage of the hydroxyethylene compounds of formula (XII) for intrathecal administration is the same as for IM administration.
The hydroxyethylene compounds of formula (XII) can be given topically. When given by this route of administration, the appropriate dosage form is a cream, ointment or patch. Because of the amount of the hydroxyethylene compounds of formula (XII) needed to administered the patch is preferred. Further, two or more patches may be needed. When administered topically, the dosage is from about 0.5 mg/day to about 200 mg/day. However, the amount that can be delivered by a patch is limited. Therefore, two or more patches may be required. The number and size of the patch is not important, what is important is that a therapeutically effective amount of the hydroxyethylene compounds of formula (XII) be delivered as is known to those skilled in the art. The hydroxyethylene compounds of formula (XII) can be administered rectally by suppository as is known to those skilled in the art. When administered by suppository, the therapeutically effective amount is from about 0.5 mg to about 500 mg.
The hydroxyethylene compounds of formula (XII) can be administered by implants as is known to those skilled in the art. When administering a hydroxyethylene compound of formula (XII) by implant, the therapeutically effective amount is the same as for depot administration.
Again, the invention here is a new method of using hydroxyethylene compounds of formula (XII) and hydroxyethylene compounds of formula (XII). Given a particular hydroxyethylene compound of formula (XII), and a desired dosage form, one skilled in the art would know how to prepare the appropriate dosage form for the hydroxyethylene compounds of formula (XII).
The hydroxyethylene compounds of formula (XII) are used in the same manner by the same routes of administration using the same pharmaceutical dosage forms and at the same dosing schedule for treating patients with MCI (mild cognitive impairment) and preventing or delaying the onset of Alzheimer""s disease in those who would progress from MCI to AD, for treating Down""s syndrome, for treating humans who have Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treating cerebral amyloid angiopathy and preventing its potential consequences, i.e. single and recurrent lobar hemorrhages, for treating other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson""s disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, diffuse Lewy body type of Alzheimer""s disease. The hydroxyethylene compounds of formula (XII) can be used with each other or with other agents used to treat or prevent the conditions listed above. Such agents include gamma-secretase inhibitors, anti-amyloid vaccines and pharmaceutical agents such as donepezil hydrochloride (ARICEPT(trademark) Tablets), tacrine hydrochloride (COGNEX(trademark) Capsules) or other acetylcholine esterase inhibitors and with direct or indirect neurotropic agents of the future.
It should be apparent to one skilled in the art that the exact dosage and frequency of administration will depend on the particular hydroxyethylene compounds of formula (XII) administered, the particular condition being treated, the severity of the condition being treated, the age, weight, general physical condition of the particular patient, and other medication the individual may be taking as is well known to administering physicians who are skilled in this art.
The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.
The chemical formulas representing various compounds or molecular fragments in the specification and claims may contain variable substituents in addition to expressly defined structural features. These variable substituents are identified by a letter or a letter followed by a numerical subscript, for example, xe2x80x9cZ1xe2x80x9d or xe2x80x9cRixe2x80x9d where xe2x80x9cixe2x80x9d is an integer. These variable substituents are either monovalent or bivalent, that is, they represent a group attached to the formula by one or two chemical bonds. For example, a group Z1 would represent a bivalent variable if attached to the formula CH3xe2x80x94C(xe2x95x90Z1)H. Groups Ri and Rj would represent monovalent variable substituents if attached to the formula CH3xe2x80x94CH2xe2x80x94C(Ri)(Rj)H2. When chemical formulas are drawn in a linear fashion, such as those above, variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis. When two or more consecutive variable substituents are enclosed in parentheses, each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses. Thus, in the formula above, both Ri and Rj are bonded to the preceding carbon atom. Also, for any molecule with an established system of carbon atom numbering, such as steroids, these carbon atoms are designated as Ci, where xe2x80x9cixe2x80x9d is the integer corresponding to the carbon atom number. For example, C6 represents the 6 position or carbon atom number in the steroid nucleus as traditionally designated by those skilled in the art of steroid chemistry. Likewise the term xe2x80x9cR6xe2x80x9d represents a variable substituent (either monovalent or bivalent) at the C6 position.
Chemical formulas or portions thereof drawn in a linear fashion represent atoms in a linear chain. The symbol xe2x80x9cxe2x80x94xe2x80x9d in general represents a bond between two atoms in the chain. Thus CH3xe2x80x94Oxe2x80x94CH2xe2x80x94CH(R1)xe2x80x94CH3 represents a 2-substituted-1-methoxypropane compound. In a similar fashion, the symbol xe2x80x9cxe2x95x90xe2x80x9d represents a double bond, e.g., CH2xe2x95x90C(Ri)xe2x80x94Oxe2x80x94CH3, and the symbol xe2x80x9cxe2x89xa1xe2x80x9d represents a triple bond, e.g., HCxe2x89xa1Cxe2x80x94CH(Ri)xe2x80x94CH2xe2x80x94CH3. Carbonyl groups are represented in either one of two ways: xe2x80x94COxe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94, with the former being preferred for simplicity.
A rigid cyclic (ring) structure for any compounds herein defines an orientation with respect to the plane of the ring for substituents attached to each carbon atom of the rigid cyclic compound. For saturated compounds which have two substituents attached to a carbon atom which is part of a cyclic system, xe2x80x94C(X1)(X2)xe2x80x94 the two substituents may be in either an axial or equatorial position relative to the ring and may change between axial/equatorial. However, the position of the two substituents relative to the ring and each other remains fixed. While either substituent at times may lie in the plane of the ring (equatorial) rather than above or below the plane (axial), one substituent is always above the other. In chemical structural formulas depicting such compounds, a substituent (X1) which is xe2x80x9cbelowxe2x80x9d another substituent (X2) will be identified as being in the alpha (xcex1) configuration and is identified by a broken, dashed or dotted line attachment to the carbon atom, i.e., by the symbol xe2x80x9c- - -xe2x80x9d or xe2x80x9c. . .xe2x80x9d. The corresponding substituent attached xe2x80x9cabovexe2x80x9d (X2) the other (X1) is identified as being in the beta (xcex2) configuration and is indicated by an unbroken line attachment to the carbon atom.
When a variable substituent is bivalent, the valences may be taken together or separately or both in the definition of the variable. For example, a variable Ri attached to a carbon atom as xe2x80x94C(xe2x95x90R,)xe2x80x94 might be bivalent and be defined as oxo or keto (thus forming a carbonyl group (xe2x80x94COxe2x80x94) or as two separately attached monovalent variable substituents xcex1xe2x80x94R1xe2x88x92j and xcex2xe2x80x94Ri-k. When a bivalent variable, Ri, is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variable is of the form xe2x80x9cxcex1xe2x80x94R1xe2x88x92j:xcex2xe2x80x94R1-kxe2x80x9d or some variant thereof. In such a case both xcex1xe2x80x94Ri-j and xcex2xe2x80x94Ri-k are attached to the carbon atom to give xe2x80x94C(xcex1xe2x80x94Ri-j)(xcex2xe2x80x94Ri-k)xe2x80x94. For example, when the bivalent variable R6, xe2x80x94C(xe2x95x90R6)xe2x80x94 is defined to consist of two monovalent variable substituents, the two monovalent variable substituents are xcex1xe2x80x94R6-1:xcex2xe2x80x94R6-2, . . . . xcex1xe2x80x94R6-9:xcex2xe2x80x94R6xe2x88x9210, etc giving xe2x80x94C(xcex1-R6xe2x88x921) (xcex2xe2x80x94R6xe2x88x922)xe2x80x94, . . . . xe2x80x94C(xcex1xe2x80x94R6xe2x88x929)(xcex2xe2x80x94R6xe2x88x9210)xe2x80x94, etc. Likewise, for the bivalent variable R11, xe2x80x94C(xe2x95x90R11)xe2x80x94, two monovalent variable substituents are xcex1xe2x80x94R11:xcex2xe2x80x94R11xe2x88x922. For a ring substituent for which separate a and 1 orientations do not exist (e.g. due to the presence of a carbon carbon double bond in the ring), and for a substituent bonded to a carbon atom which is not part of a ring the above convention is still used, but the xcex1 and xcex2 designations are omitted.
Just as a bivalent variable may be defined as two separate monovalent variable substituents, two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable. For example, in the formula xe2x80x94C1(Ri)Hxe2x80x94C2(Rj)Hxe2x80x94 (C1 and C2 define arbitrarily a first and second carbon atom, respectively) Ri and Rj may be defined to be taken together to form (1) a second bond between C1 and C2 or (2) a bivalent group such as oxa (xe2x80x94Oxe2x80x94) and the formula thereby describes an epoxide. When Ri and Rj are taken together to form a more complex entity, such as the group xe2x80x94Xxe2x80x94Yxe2x80x94, then the orientation of the entity is such that C, in the above formula is bonded to X and C2 is bonded to Y. Thus, by convention the designation xe2x80x9c . . . Ri and Rj are taken together to form xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94COxe2x80x94 . . . xe2x80x9d means a lactone in which the carbonyl is bonded to C2. However, when designated xe2x80x9c . . . Rj and Ri are taken together to form xe2x80x94COxe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94 the convention means a lactone in which the carbonyl is bonded to C1.
The carbon atom content of variable substituents is indicated in one of two ways. The first method uses a prefix to the entire name of the variable such as xe2x80x9cC1-C4xe2x80x9d, where both xe2x80x9c1 xe2x80x9d and xe2x80x9c4xe2x80x9d are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, xe2x80x9cC1-C4 alkylxe2x80x9d represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given). Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defined. Thus C2-C4 alkoxycarbonyl describes a group CH3xe2x80x94(CH2)nxe2x80x94Oxe2x80x94COxe2x80x94 where n is zero, one or two. By the second method the carbon atom content of only each portion of the definition is indicated separately by enclosing the xe2x80x9cCi-Cjxe2x80x9d designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined. By this optional convention (C1-C3)alkoxycarbonyl has the same meaning as C2-C4 alkoxycarbonyl because the xe2x80x9cC1-C3xe2x80x9d refers only to the carbon atom content of the alkoxy group. Similarly while both C2-C6 alkoxyalkyl and (C1-C3)alkoxy(C1-C3)alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms, the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms.
When the claims contain a fairly complex (cyclic) substituent, at the end of the phrase naming/designating that particular substituent will be a notation in (parentheses) which will correspond to the same name/designation in one of the CHARTS which will also set forth the chemical structural formula of that particular substituent.
It is to be understood that the recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within that range (e.g. 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5).
It is to be understood that all numbers and fractions thereof are presumed to be modified by the term xe2x80x9cabout.xe2x80x9d
It is to be understood that xe2x80x9caxe2x80x9d as used herein includes both the singular and plural.
The general definitions used herein have the following meanings within the scope of the present invention.
All temperatures are in degrees Celsius.
TLC refers to thin-layer chromatography.
psi refers to pounds/in2.
HPLC refers to high pressure liquid chromatography.
THF refers to tetrahydrofuran.
DMF refers to dimethylformamide.
EDC refers to ethyl-1-(3-dimethylaminopropyl)carbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
NBS refers to N-bromosuccinimide.
TEA refers to triethylamine.
BOC refers to 1,1-dimethylethoxy carbonyl or t-butoxycarbonyl, xe2x80x94COxe2x80x94Oxe2x80x94C(CH3)3.
CBZ refers to benzyloxycarbonyl, xe2x80x94COxe2x80x94Oxe2x80x94CH2-xcfx86.
TFA refers to trifluoracetic acid, CF3xe2x80x94COOH.
CDI refers to 1,1xe2x80x2-carbonyldiimidazole.
Saline refers to an aqueous saturated sodium chloride solution.
Chromatography (column and flash chromatography) refers to purification/separation of compounds expressed as (support, eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s).
CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts are reported in ppm (xcex4) downfield from TMS.
NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (d) downfield from TMS.
-xcfx86 refers to phenyl (C6H5).
MS refers to mass spectrometry expressed as m/e, m/z or mass/charge unit. MH+ refers to the positive ion of a parent plus a hydrogen atom. EI refers to electron impact. CI refers to chemical ionization. FAB refers to fast atom bombardment.
HRMS refers to high resolution mass spectrometry.
Ether refers to diethyl ether.
Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).
When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt/v).
BOP refers to benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate.
TBDMSC1 refers to t-butyldimethylsilyl chloride.
TBDMSOTf refers to t-butyldimethylsilyl trifluosulfonic acid ester.
Trisomy 21 refers to Down""s Syndrome.
Ac=acetyl (methylcarbonyl)
aq.=aqueous
bd=broad doublet
bs=broad singlet
c=concentration (g/mL)
cc=cubic centimeter
d=doublet
DCM=dichloromethane=methylene chloride=CH2Cl2 
de=diastereomeric excess
EDTA=ethylene diamine tetraacetic acid
eq.=equivalents
EtOAc=ethyl acetate
EtOH=ethanol
g=grams
HOBT=1-hydroxybenzotriazole
h=hour
IC50=inhibitory concentration of a compound that reduces enzyme activity by half.
iso=an alkyl chain having the ending group 2-methylpropyl, i.e. xe2x80x94CH(CH3)2.
IM=intramuscularly
IV=intravenously
SCxe2x89xa1subcutaneously
L=liter
LDA=lithium diisopropyl amide
m=multiplet
max=maximum
mg=milligram
mL=milliliter
mm=millimeter
mM=millimolar
mmol=millimole
mp=melting point
MeOH=methanol
meq=milliequivalent
MsOH=methanesulfonic acid
n=normal, i.e. unbranched, e.g. n-Pr is xe2x80x94CH2xe2x80x94CH2xe2x80x94CH3 
N=normal
ng=nanogram
m=nanometers
OD=optical density
PEPCxe2x89xa11-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide
pg=picogram
pM=picoMolar
Rf=ratio of movement of a substance on a thin layer chromatogram in comparison to the movement of the solvent front.
xcex4=units of measurement in nuclear magnetic resonance spectroscopy which are relative to a standard, e.g. tetramethyl silane.
q=quartet
quint.=quintet
rpm=rotations per minute
s=singlet
t=triplet
t or tert=tertiary in an alkyl chain, e.g. t-butyl is xe2x80x94C(CH3)3.
xcexcL=microliter
xcexcM=micromolar (an expression of concentration in micromoles/liter)
s=singlet
t=triplet
UV=ultraviolet
Unless otherwise indicated, all functional group radicals (e.g., alkyl, aryl, cycloalkyl, cyclic heteroaryl, heterocycle, etc.) can be substituted or unsubstituted. Substituted functional group radicals can be substituted with one or more substituents, unless indicated otherwise. Suitable substituents for substituted functional group radicals generally include halogen, hydroxy, alkoxy, alkyl, aryl, arylalkyl, alkylaryl, arylalkoxy, and the like. It will be understood that the terminology xe2x80x9cX radical substituted by a/an Yxe2x80x9d includes the xe2x80x9cXxe2x80x9d radical being substituted by two or more xe2x80x9cYxe2x80x9d, unless indicated otherwise.
xe2x80x9cAlkylxe2x80x9d refers to linear or branched, saturated aliphatic hydrocarbon radicals, such as, for example, methyl, ethyl, propyl, butyl, octyl, isopropyl, tert-butyl, sec-pentyl, and the like.
xe2x80x9cCycloalkylxe2x80x9d refers to cyclic aliphatic hydrocarbon radicals, such as, for example, 3- to 8-member hydrocarbon rings (e.g., cyclohexyl or cyclopentyl), bicyclic 4- to 10-member hydrocarbon ring systems, and a tricyclic 8- to 14-member hydrocarbon ring systems. Monocyclic cycloalkyl groups include, for example, cyclohexane and cyclopentane. Multicyclic cycloalkyl groups include cyclohexyl, cyclopentyl, and 1, 2, 3, 4-tetrahydrohaphthyl for example.
xe2x80x9cHeterocyclexe2x80x9d refers to cyclic, non-aromatic radicals containing at least two carbon atoms and 1 to 3 heteroatoms selected from O, N, and S as members of at least one ring. Examples of such radicals include 3- to 8-member rings; bicyclic 4- to 10-member ring systems, and tricyclic 8- to 14-member ring systems, where at least one ring (and in some instances each of the rings) of any of these examples contains 1 to 3 heteroatoms selected from O, N, and S as members of the ring. Monocyclic heterocyclic groups include morpholinyl, piperazinyl, and tetrahydrofuranyl, for example. Multicyclic heterocyclic groups include decahydroquinoline, cyclohexene oxide, and 3-amino-3-azabicyclo [3.3.0] octane, for example.
xe2x80x9cAlkylenexe2x80x9d refers to bivalent, linear or branched, saturated aliphatic hydrocarbon radicals, such as, for example, methylene, ethylene, propylene, butylene, octylene, isopropylene, tert-butylene, sec-pentylene, and the like.
xe2x80x9cAlkenylxe2x80x9d refers to linear or branched aliphatic hydrocarbon radicals containing at least one double bond, such as, for example, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-methyl-1-propenyl, and the like.
xe2x80x9cAlkynylxe2x80x9d refers to linear or branched aliphatic hydrocarbon radicals containing at least one triple bond, such as, for example, ethynyl (acetyl), 1-propynyl, 2-propynyl, 1-butynyl, and the like.
xe2x80x9cArylxe2x80x9d refers to cyclic aromatic hydrocarbon radicals having a single ring, such as phenyl, multiple rings, such as biphenyl, and multiple condensed rings, such as naphthyl and anthryl. Monocyclic aryl groups include phenyl, for example. Multicyclic aryl groups include naphthyl and anthryl, for example.
xe2x80x9cAminexe2x80x9d includes primary, secondary and tertiary amines which may be in straight or branched chains or, in the case of secondary and tertiary amines within rings (e.g. morpholine and piperazine).
xe2x80x9cHeteroarylxe2x80x9d refers to a cyclic aromatic rings having 1 to 4 hetero atoms selected from S, O, and N; and aromatic 7 to 10 membered organic stable bicyclic rings having 1 to 5 hetero atoms selected from S, O, and N. Examples of such radicals include 3- to 8-member rings; bicyclic 4- to 10-member ring systems; and tricyclic 8- to 14-member ring systems, where at least one ring (and in some instances each of the rings) of any of these examples contains 1 to 3 heteroatoms selected from O, N, and S as members of the ring.
xe2x80x9cAcyloxyxe2x80x9d refers to the groups Rxe2x80x94C(O)Oxe2x80x94, substituted Rxe2x80x94C(O)Oxe2x80x94, cycloalkyl-C(O)Oxe2x80x94, arylxe2x80x94C(O)Oxe2x80x94, and heterocyclicxe2x80x94C(O)O where R=alkyl, and alkyl, cycloalkyl, aryl, and heterocyclic are as defined herein.
xe2x80x9cAcylaminoxe2x80x9d refers to the groups Rxe2x80x94C(O)Nxe2x80x94, substituted Rxe2x80x94C(O)Nxe2x80x94, cycloalkyl-C(O)Nxe2x80x94, arylxe2x80x94C(O)Nxe2x80x94, and heterocyclicxe2x80x94C(O)Nxe2x80x94where R=alkyl, and alkyl, cycloalkyl, aryl, and heterocyclic are as defined herein.
xe2x80x9cAmidexe2x80x9d and xe2x80x9camidoxe2x80x9d refer to a functional group containing a carbon atom double-bonded to an oxygen atom and additionally singly bonded to a nitrogen atom [xe2x80x94C(O)xe2x80x94N]. xe2x80x9cPrimaryxe2x80x9d amide describes an unsubstituted amide group [xe2x80x94C(O)xe2x80x94NH2]. xe2x80x9cSecondaryxe2x80x9d and xe2x80x9ctertiaryxe2x80x9d amides are amides in which nitrogen is substituted with one and two non-hydrogen groups respectively. The term xe2x80x9clactamxe2x80x9d refers to a cyclized amide, i.e. a secondary or tertiary amide wherein the carbonyl carbon and the nitrogen atom are adjacent members of a ring.
xe2x80x9cHalogenxe2x80x9d refers to fluoro, chloro, bromo, and iodo radicals.
xe2x80x9cLactonexe2x80x9d refers to cyclized ester of a carboxylic acid.
xe2x80x9cThioxe2x80x9d refers to the replacement of oxygen by sulfur in a defined radical. Examples of thio compound include alkylthioxy compounds (e.g. alkylxe2x80x94Sxe2x80x94).
xe2x80x9cThioxyalkylxe2x80x9d refers to the divalent radical xe2x80x94Sxe2x80x94alkyl-, where alkyl is as defined above. Examples of thioxyalkyl moietites include alkyl-S-alkyl moieties, such as CH3xe2x80x94Sxe2x80x94CH2CH2xe2x80x94.
xe2x80x9cAlkoxyxe2x80x9d refers to the radical xe2x80x94Oxe2x80x94alkyl with alkyl as defined above. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, and the like.
xe2x80x9cArylalkylxe2x80x9d and xe2x80x9caralkylxe2x80x9d refer to an alkyl radical substituted with an aryl.
xe2x80x9cAlkylarylxe2x80x9d refers to an aryl radical substituted with an alkyl.
All the terms xe2x80x9ccarboxylxe2x80x9d, xe2x80x9ccarboxylic acidxe2x80x9d, xe2x80x9ccarboxylatexe2x80x9d and xe2x80x9ccarbamoylxe2x80x9d are terms referring to functional groups containing a carbon atom double-bonded to an oxygen atom [Cxe2x95x90O, also called an acyl or a carbonyl group, represented in linear notation as xe2x80x94C(O)xe2x80x94] and additionally single- bonded to another oxygen atom [xe2x80x94C(O)xe2x80x94Oxe2x80x94], and in the case of carbamoyl, additionally a nitrogen atom is also bonded to the carbonyl carbon to give xe2x80x94Nxe2x80x94C(O)xe2x80x94Oxe2x80x94. Carboxyl, carboxylate and carbamate include the corresponding pharmaceutically acceptable C1-C6 alkyl and C6-C10 aryl esters and secondary and tertiary amides.
Combinations of these terms for functional group radicals are also used. Typically, the last term in the designation contains the radical that bonds to the remainder of the chemical structure. For example, xe2x80x9chaloalkylxe2x80x9d refers to an alkyl radical substituted by a halogen, xe2x80x9ccycloalkylalkylxe2x80x9d refers to alkyl radical substituted by a cycloalkyl, and xe2x80x9calkylcycloalkylxe2x80x9d refers to a cycloalkyl radical substituted by an alkyl. 